Anthelmintic compounds and compositions and method of using thereof

ABSTRACT

The present invention relates to novel anthelmintic compounds of formula (I) below: 
     
       
         
         
             
             
         
       
     
     wherein
         Y and Z are independently a bicyclic carbocyclic or a bicyclic heterocyclic group, or one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic group and the other of Y or Z is alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl, and variables X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7  and X 8  are as defined herein. The invention also provides for veterinary compositions comprising the anthelmintic compounds of the invention, and their uses for the treatment and prevention of parasitic infections in animals.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of priority to U.S. ProvisionalPatent Application No. 61/728,782 filed Nov. 20, 2012, which isincorporated herein by reference in its entirety.

INCORPORATION BY REFERENCE

The foregoing applications and all documents cited therein or duringtheir prosecution (“application cited documents”) and all documentscited or referenced in the application cited documents, and alldocuments cited or referenced herein (“herein cited documents”), and alldocuments cited or referenced in herein cited documents, together withany manufacturer's instructions, descriptions, product specifications,and product sheets for any products mentioned herein or in any documentincorporated by reference herein, are hereby incorporated herein byreference, and may be employed in the practice of the invention.

FIELD OF THE INVENTION

The present invention relates to novel anthelmintic compounds of formula(I) and compositions containing the compounds:

wherein, at least one of variables Y and Z is a bicyclic carbocyclyl orheterocyclyl group. Variables Y, X₁, X₂, X₃, X₄, X₅, X₆, X₇, X₈ and Zare as defined below. The invention also relates to parasiticidalcompositions comprising the compounds, and methods and uses of thecompounds for treating and preventing parasitic infections andinfestations in animals.

BACKGROUND OF THE INVENTION

Animals such as mammals and birds are often susceptible to parasiteinfestations/infections. These parasites may be ectoparasites, such asinsects, and endoparasites such as nematodes and other worms.Domesticated animals, such as cats and dogs, are often infested with oneor more of the following ectoparasites:

-   -   fleas (e.g. Ctenocephalides spp., such as Ctenocephalides felis        and the like);    -   ticks (e.g. Rhipicephalus spp., Ixodes spp., Dermacentor spp.,        Amblyoma spp., and the like);    -   mites (e.g. Demodex spp., Sarcoptes spp., Otodectes spp., and        the like);    -   lice (e.g. Trichodectes spp., Cheyletiella spp., Linognathus        spp. and the like);    -   mosquitoes (Aedes spp., Culex spp., Anopheles spp. and the        like); and    -   flies (Hematobia spp., Musca spp., Stomoxys spp., Dermatobia        spp., Cochliomyia spp. and the like).

Fleas are a particular problem because not only do they adversely affectthe health of the animal or human, but they also cause a great deal ofpsychological stress. Moreover, fleas may also transmit pathogenicagents to animals and humans, such as tapeworm (Dipylidium caninum).

Similarly, ticks are also harmful to the physical and psychologicalhealth of the animal or human. However, the most serious problemassociated with ticks is that they are vectors of pathogenic agents inboth humans and animals. Major diseases which may be transmitted byticks include borrelioses (Lyme disease caused by Borrelia burgdorferi),babesioses (or piroplasmoses caused by Babesia spp.) and rickettsioses(e.g. Rocky Mountain spotted fever). Ticks also release toxins whichcause inflammation or paralysis in the host. Occasionally, these toxinsare fatal to the host.

Likewise, farm animals are also susceptible to parasite infestations.For example, cattle are affected by a large number of parasites.Parasites prevalent among cattle in some regions are ticks of the genusRhipicephalus, especially those of the species microplus (cattle tick),decoloratus and annulatus. Ticks such as Rhipicephalus microplus(formerly Boophilus microplus) are difficult to control because they layeggs in the pasture where farm animals graze. This species of ticks isconsidered a one-host tick and spends immature and adult stages on oneanimal before the female engorges and falls off the host to lay eggs inthe environment. The life cycle of the tick is approximately three tofour weeks. In addition to cattle, Rhipicephalus microplus may infestbuffalo, horses, donkeys, goats, sheep, deer, pigs, and dogs. A heavytick burden on animals can decrease production and damage hides as wellas transmit diseases such as babesioses (“cattle fever”) andanaplasmosis.

Animals and humans also suffer from endoparasitic infections including,for example, helminthiasis which is caused by of parasitic wormscategorized as cestodes (tapeworm), nematodes (roundworm) and trematodes(flatworm or flukes). These parasites adversely affect the nutrition ofthe animal and cause severe economic losses in pigs, sheep, horses, andcattle as well as affecting domestic animals and poultry. Otherparasites which occur in the gastrointestinal tract of animals andhumans include Ancylostoma, Necator, Ascaris, Strongyloides,Trichinella, Capillaria, Toxocara, Toxascaris, Trichiris, Enterobius andparasites which are found in the blood or other tissues and organs suchas filarial worms and the extra intestinal stages of Strogyloides,Toxocara and Trichinella.

Another endoparasite which seriously harms animals is Dirofilariaimmitis, also known as Heartworm. The most common hosts are dogs andcats but other animals such as ferrets and raccoons may also beinfected. The parasitic worm is transmitted by the mosquitoe bites,which carry the heartworm larvae. The adult worms live in the majorblood vessels of the lung, causing inflammation of the blood vessels andpotentially resulting in heart damage and early death. In advancedinfections, the worms enter the heart as well.

Recently, anthelmintic compounds with activity against variousendoparasitic species were reported in WO 2009/077527 A1, WO 2010/115688A1, WO 2010/146083 A1 and EP 2 468 096 A1 (all incorporated herein byreference). Although many parasitic infections can be treated with knownantiparasitic compounds and compositions, there is a need for newparasiticidal active agents and veterinary compositions and methods withimproved efficacy, bioavailability, and spectrum of coverage to protectanimals against endoparasites and/or ectoparasites. This inventionaddresses this need.

SUMMARY OF THE INVENTION

The present invention is directed to novel and inventive anthelminticcompounds of formulae (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2),(IB-3), (IB-4), (IC) and (IC-1):

as described herein and compositions comprising the compounds incombination with a pharmaceutically acceptable carrier or diluent.

The present invention is also directed to methods for the treatment andprevention of a parasitic infection in an animal comprisingadministering at least one of the compounds of the invention to theanimal. Also included in the present invention are uses of the compoundsfor the treatment and/or prevention of parasitic infections in animalsand the use of the compounds in the preparation of a medicament for thetreatment and/or prevention of a parasitic infection in an animal.

The compounds of the invention are intended to encompass racemicmixtures, specific stereoisomers and tautomeric forms of the compound.Another aspect of the invention is a salt form of the compound of theinvention.

Another aspect of the invention are solid state forms of the compoundsof the invention which consists of crystalline forms including singlecrystals, nanocrystals, co-crystals, molecular complexes, hydrates,anhydrates, solvates, desolvates, clathrates and inclusion complexes andnon-crystalline forms including non-crystalline glass andnon-crystalline amorphous forms.

It is noted that the invention does not intend to encompass within thescope of the invention any previously disclosed product, process ofmaking the product or method of using the product, which meets thewritten description and enablement requirements of the USPTO (35 U.S.C.112, first paragraph) or the EPO (Article 83 of the EPC), such thatapplicant(s) reserve the right and hereby disclose a disclaimer of anypreviously described product, method of making the product or process ofusing the product.

It is further noted that in this disclosure and particularly in theclaims and/or paragraphs, terms such as “comprises”, “comprised”,“comprising” and the like can have the meaning attributed to it in U.S.Patent law; e.g., they can mean “includes”, “included”, “including”, andthe like; and that terms such as “consisting essentially of” and“consists essentially of” have the meaning ascribed to them in U.S.Patent law, e.g., they allow for elements not explicitly recited, butexclude elements that are found in the prior art or that affect a basicor novel characteristic of the invention.

These and other embodiments are disclosed or are apparent from andencompassed by, the following Detailed Description.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel and inventive anthelminticcompounds of formulae (I), (IA), (IA-1), (IA-2), (IB), (IB-1), (IB-2),(IB-3), (IB-4), (IC) and (IC-1) as described herein, and compositionscomprising the compounds together with a pharmaceutically acceptablecarrier or diluent. The compounds of the invention have been found to behighly efficacious against internal parasites (endoparasites) that causeharm to animals. In certain embodiments, the compounds of the inventionmay also be used to combat external parasites (ectoparasites) that causeharm to animals.

The compounds may be combined with one or more additional active agentsin compositions to broaden the scope of coverage against bothendoparasites and ectoparasites.

Also provided are methods and uses of the compounds and compositions forthe treatment and/or prophylaxis of parasitic infections andinfestations of animals, comprising administering an effective amount ofa compound or composition of the invention to the animal.

DEFINITIONS

Terms used herein will have their customary meaning in the art unlessspecified otherwise. The organic moieties mentioned in the definitionsof the variables of formula (I) are—like the term halogen—collectiveterms for individual listings of the individual group members. Theprefix C_(n)-C_(m) indicates in each case the possible number of carbonatoms in the group.

The term “animal” is used herein to include all mammals, birds and fishand also include all vertebrate animals. Animals include, but are notlimited to, cats, dogs, cattle, chickens, cows, deer, goats, horses,llamas, pigs, sheep and yaks. It also includes an individual animal inall stages of development, including embryonic and fetal stages. In someembodiments, the animal will be a non-human animal.

Unless otherwise specifically noted or apparent by context, “activeagent” or “active ingredient” or “therapeutic agent” as used in thisspecification, means an anthelmintic compound of the invention.

The term “fatty acid” refers to carboxylic acids having from 4 to 26carbon atoms.

The terms “fatty alcohol” or “long-chain aliphatic alcohol” refer toaliphatic alcohols containing from 6 to 20 carbon atoms.

The term “alkyl” refers to saturated straight, branched, cyclic,primary, secondary or tertiary hydrocarbons, including those having 1 to20 atoms. In some embodiments, alkyl groups will include C₁-C₁₂, C₁-C₁₀,C₁-C₈, C₁-C₆ or C₁-C₄ alkyl groups. Examples of C₁-C₁₀ alkyl include,but are not limited to, methyl, ethyl, propyl, 1-methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1-methylbutyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl,1-ethylpropyl, hexyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl,1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,2,2-dimethylbutyl, 2,3-dimethylbutyl, 3,3-dimethylbutyl, 1-ethylbutyl,2-ethylbutyl, 1,1,2-trimethylpropyl, 1,2,2-trimethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, heptyl, octyl,2-ethylhexyl, nonyl and decyl and their isomers. C₁-C₄-alkyl means forexample methyl, ethyl, propyl, 1-methylethyl, butyl, 1-methylpropyl,2-methylpropyl or 1,1-dimethylethyl.

The term “carbocyclyl” refers to carbon-containing ring systems,including both “cycloalkyl” and “aryl” groups as defined herein.

Cyclic alkyl groups or “cycloalkyl”, which are encompassed by alkylinclude those with 3 to 10 carbon atoms having single or multiplecondensed rings. In some embodiments, cycloalkyl groups include C₄-C₇ orC₃-C₄ cyclic alkyl groups. Non-limiting examples of cycloalkyl groupsinclude adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl and the like.

The alkyl groups described herein can be unsubstituted or substitutedwith one or more moieties selected from the group consisting of alkyl,alkenyl, alkynyl, alkoxy, haloalkoxy, aryl, aryloxy, arylalkoxy,heteroaryl, heteroaryloxy, heteroarylalkoxy, halogen, haloalkyl,hydroxyl, hydroxyalkyl, carboxyl, alkylcarbonyl, arylcarbonyl,alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl,dialkylaminocarbonyl, acyl, acyloxy, sulfanyl, sulfamonyl, amino, alkyl-or dialkylamino, amido, arylamino, alkoxy, haloalkoxy, aryloxy, nitro,cyano, azido, thiol, imino, sulfonic acid; alkyl, haloalkyl or arylsulfate; alkyl, haloalkyl or aryl sulfonyl; arylalkylsulfonyl; alkyl,haloalkyl or aryl sulfinyl; arylalkylsulfinyl; alkyl haloalkyl or arylthio; arylalkylthio; heteroarylthio, heteroarylalkylthio,heteroarylsulfinyl, heteroarylalkylsulfinyl, heteroarylsulfonyl,heteroarylalkylsulfonyl, an alkyl, haloalkyl or aryl ester, phosphonyl,phosphinyl, phosphoryl, phosphine, thioester, thioether, acid halide,anhydride, oxime, hydrazine, carbamate, phosphoric acid, phosphate,phosphonate, or any other viable functional group that does not inhibitthe biological activity of the compounds of the invention, eitherunprotected, or protected as necessary, as known to those skilled in theart, for example, as taught in Greene, et al., Protective Groups inOrganic Synthesis, John Wiley and Sons, Third Edition, 1999, herebyincorporated by reference.

Terms including the term “alkyl” such as “alkylcycloalkyl,”“cycloalkylalkyl,” “alkylamino,” or “dialkylamino” will be understood tocomprise an alkyl group as defined above linked to the other functionalgroup, where the group is linked to the compound through the last grouplisted, as understood by those of skill in the art.

The term “alkenyl” refers to both straight and branched carbon chainswhich have at least one carbon-carbon double bond. In some embodiments,alkenyl groups may include C₂-C₂₀ alkenyl groups. In other embodiments,alkenyl includes C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkenyl groups.In one embodiment of alkenyl, the number of double bonds is 1-3, inanother embodiment of alkenyl, the number of double bonds is one or two.Other ranges of carbon-carbon double bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. “C₂-C₁₀-alkenyl” groups may include more than one double bondin the chain. Examples include, but are not limited to, ethenyl,1-propenyl, 2-propenyl, 1-methyl-ethenyl, 1-butenyl, 2-butenyl,3-butenyl, 1-methyl-1-propenyl, 2-methyl-1-propenyl,1-methyl-2-propenyl, 2-methyl-2-propenyl; 1-pentenyl, 2-pentenyl,3-pentenyl, 4-pentenyl, 1-methyl-1-butenyl, 2-methyl-1-butenyl,3-methyl-1-butenyl, 1-methyl-2-butenyl, 2-methyl-2-butenyl,3-methyl-2-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl,3-methyl-3-butenyl, 1,1-dimethyl-2-propenyl, 1,2-dimethyl-1-propenyl,1,2-dimethyl-2-propenyl, 1-ethyl-1-propenyl, 1-ethyl-2-propenyl,1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl,1-methyl-1-pentenyl, 2-methyl-1-pentenyl, 3-methyl-1-pentenyl,4-methyl-1-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,3-methyl-2-pentenyl, 4-methyl-2-pentenyl, 1-methyl-3-pentenyl,2-methyl-3-pentenyl, 3-methyl-3-pentenyl, 4-methyl-3-pentenyl,1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 3-methyl-4-pentenyl,4-methyl-4-pentenyl, 1,1-dimethyl-2-butenyl, 1,1-dimethyl-3-butenyl,1,2-dimethyl-1-butenyl, 1,2-dimethyl-2-butenyl, 1,2-dimethyl-3-butenyl,1,3-dimethyl-1-butenyl, 1,3-dimethyl-2-butenyl, 1,3-dimethyl-3-butenyl,2,2-dimethyl-3-butenyl, 2,3-dimethyl-1-butenyl, 2,3-dimethyl-2-butenyl,2,3-dimethyl-3-butenyl, 3,3-dimethyl-1-butenyl, 3,3-dimethyl-2-butenyl,1-ethyl-1-butenyl, 1-ethyl-2-butenyl, 1-ethyl-3-butenyl,2-ethyl-1-butenyl, 2-ethyl-2-butenyl, 2-ethyl-3-butenyl,1,1,2-trimethyl-2-propenyl, 1-ethyl-1-methyl-2-propenyl,1-ethyl-2-methyl-1-propenyl and 1-ethyl-2-methyl-2-propenyl.

“Alkynyl” refers to both straight and branched carbon chains which haveat least one carbon-carbon triple bond. In one embodiment of alkynyl,the number of triple bonds is 1-3; in another embodiment of alkynyl, thenumber of triple bonds is one or two. In some embodiments, alkynylgroups include from C₂-C₂₀ alkynyl groups. In other embodiments, alkynylgroups may include C₂-C₁₂, C₂-C₁₀, C₂-C₈, C₂-C₆ or C₂-C₄ alkynyl groups.Other ranges of carbon-carbon triple bonds and carbon numbers are alsocontemplated depending on the location of the alkenyl moiety on themolecule. For example, the term “C₂-C₁₀-alkynyl” as used herein refersto a straight-chain or branched unsaturated hydrocarbon group having 2to 10 carbon atoms and containing at least one triple bond, such asethynyl, prop-1-yn-1-yl, prop-2-yn-1-yl, n-but-1-yn-1-yl,n-but-1-yn-3-yl, n-but-1-yn-4-yl, n-but-2-yn-1-yl, n-pent-1-yn-1-yl,n-pent-1-yn-3-yl, n-pent-1-yn-4-yl, n-pent-1-yn-5-yl, n-pent-2-yn-1-yl,n-pent-2-yn-4-yl, n-pent-2-yn-5-yl, 3-methylbut-1-yn-3-yl,3-methylbut-1-yn-4-yl, n-hex-1-yn-1-yl, n-hex-1-yn-3-yl,n-hex-1-yn-4-yl, n-hex-1-yn-5-yl, n-hex-1-yn-6-yl, n-hex-2-yn-1-yl,n-hex-2-yn-4-yl, n-hex-2-yn-5-yl, n-hex-2-yn-6-yl, n-hex-3-yn-1-yl,n-hex-3-yn-2-yl, 3-methylpent-1-yn-1-yl, 3-methylpent-1-yn-3-yl,3-methylpent-1-yn-4-yl, 3-methylpent-1-yn-5-yl, 4-methylpent-1-yn-1-yl,4-methylpent-2-yn-4-yl or 4-methylpent-2-yn-5-yl and the like.

The term “haloalkyl” refers to an alkyl group, as defined herein, whichis substituted by one or more halogen atoms. For example C₁-C₄-haloalkylincludes, but is not limited to, chloromethyl, bromomethyl,dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl,trifluoromethyl, chlorofluoromethyl, dichlorofluoromethyl,chlorodifluoromethyl, 1-chloroethyl, 1-bromoethyl, 1-fluoroethyl,2-fluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl,2-chloro-2-fluoroethyl, 2-chloro-2,2-difluoroethyl,2,2-dichloro-2-fluoroethyl, 2,2,2-trichloroethyl, pentafluoroethyl andthe like.

The term “haloalkenyl” refers to an alkenyl group, as defined herein,which is substituted by one or more halogen atoms.

The term “haloalkynyl” refers to an alkynyl group, as defined herein,which is substituted by one or more halogen atoms.

“Alkoxy” refers to alkyl-O—, wherein alkyl is as defined above.Similarly, the terms “alkenyloxy,” “alkynyloxy,” “haloalkoxy,”“haloalkenyloxy,” “haloalkynyloxy,” “cycloalkoxy,” “cycloalkenyloxy,”“halocycloalkoxy,” and “halocycloalkenyloxy” refer to the groupsalkenyl-O—, alkynyl-O—, haloalkyl-O—, haloalkenyl-O—, haloalkynyl-O—,cycloalkyl-O—, cycloalkenyl-O—, halocycloalkyl-O—, andhalocycloalkenyl-O—, respectively, wherein alkenyl, alkynyl, haloalkyl,haloalkenyl, haloalkynyl, cycloalkyl, cycloalkenyl, halocycloalkyl, andhalocycloalkenyl are as defined above. Examples of C₁-C₆-alkoxy include,but are not limited to, methoxy, ethoxy, C₂H₅—CH₂O—, (CH₃)₂CHO—,n-butoxy, C₂H₅—CH(CH₃)O—, (CH₃)₂CH—CH₂O—, (CH₃)₃CO—, n-pentoxy,1-methylbutoxy, 2-methylbutoxy, 3-methylbutoxy, 1,1-dimethylpropoxy,1,2-dimethylpropoxy, 2,2-dimethyl-propoxy, 1-ethylpropoxy, n-hexoxy,1-methylpentoxy, 2-methylpentoxy, 3-methylpentoxy, 4-methylpentoxy,1,1-dimethylbutoxy, 1,2-dimethylbutoxy, 1,3-dimethylbutoxy,2,2-dimethylbutoxy, 2,3-dimethylbutoxy, 3,3-dimethylbutoxy,1-ethylbutoxy, 2-ethylbutoxy, 1,1,2-trimethylpropoxy,1,2,2-trimethylpropoxy, 1-ethyl-1-methylpropoxy, 1-ethyl-2-methylpropoxyand the like.

The term “alkylthio” refers to alkyl-S—, wherein alkyl is as definedabove. Similarly, the terms “haloalkylthio,” “cycloalkylthio,” and thelike, refer to haloalkyl-S— and cycloalkyl-S— where haloalkyl andcycloalkyl are as defined above.

The term “halothio” refers to (halogen)₅-S—, wherein halogen is asdefined above. An example of “halothio” is the group F₅S—.

The term “alkylsulfinyl” refers to alkyl-S(O)—, wherein alkyl is asdefined above.

Similarly, the term “haloalkylsulfinyl” refers to haloalkyl-S(O)— wherehaloalkyl is as defined above.

The term “alkylsulfonyl” refers to alkyl-S(O)₂—, wherein alkyl is asdefined above. Similarly, the term “haloalkylsulfonyl” refers tohaloalkyl-S(O)₂— where haloalkyl is as defined above.

The term alkylamino and dialkylamino refer to alkyl-NH— and (alkyl)₂N—where alkyl is as defined above. Similarly, the terms “haloalkylamino”refers to haloalkyl-NH— where haloalkyl is as defined above.

The terms “alkylcarbonyl,” “alkoxycarbonyl,” “alkylaminocarbonyl,” and“dialkylaminocarbonyl” refer to alkyl-C(O)—, alkoxy-C(O)—,alkylamino-C(O)— and dialkylamino-C(O)— where alkyl, alkoxy, alkylaminoand dialkylamino are as defined above. Similarly, the terms“haloalkylcarbonyl,” “haloalkoxycarbonyl,” “haloalkylaminocarbonyl,” and“dihaloalkylaminocarbonyl” refer to the groups haloalkyl-C(O)—,haloalkoxy-C(O)—, haloalkylamino-C(O)— and dihaloalkylamino-C(O)— wherehaloalkyl, haloalkoxy, haloalkylamino and dihaloalkylamino are asdefined above.

“Aryl” refers to a monovalent aromatic carbocyclic group of from 6 to 14carbon atoms having a single ring or multiple condensed rings. In someembodiments, aryl groups include C₆-C₁₀ aryl groups. Aryl groupsinclude, but are not limited to, phenyl, biphenyl, naphthyl,tetrahydronaphthyl, phenylcyclopropyl, biphenylene, fluorene,anthracene, acenaphthene, phenanthrene and indanyl. Examples of bicyclicaryl groups include naphthyl and indanyl. Aryl groups may beunsubstituted or substituted by one or more moieties selected fromhalogen, cyano, nitro, hydroxy, mercapto, amino, alkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, haloalkenyl, haloalkynyl,halocycloalkyl, halocycloalkenyl, alkoxy, alkenyloxy, alkynyloxy,haloalkoxy, haloalkenyloxy, haloalkynyloxy, cycloalkoxy,cycloalkenyloxy, halocycloalkoxy, halocycloalkenyloxy, alkylthio,haloalkylthio, cycloalkylthio, halocycloalkylthio, alkylsulfinyl,alkenylsulfinyl, haloalkylsulfinyl, haloalkenylsulfinyl,haloalkynylsulfinyl, alkylsulfonyl, alkenylsulfonyl, alkynylsulfonyl,haloalkyl-sulfonyl, haloalkenylsulfonyl, haloalkynylsulfonyl,alkylamino, alkenylamino, alkynylamino, di(alkyl)amino,di(alkenyl)-amino, di(alkynyl)amino, or trialkylsilyl.

The terms “aralkyl” or “arylalkyl” refers to an aryl group that isbonded to the parent compound through a diradical alkylene bridge,(—CH₂—)₆, where n is 1-12 and where “aryl” is as defined above.

“Heteroaryl” refers to a monovalent aromatic group of from 1 to 15carbon atoms, preferably from 1 to 10 carbon atoms, having one or moreoxygen, nitrogen, and sulfur heteroatoms within the ring, preferably 1to 4 heteroatoms, or 1 to 3 heteroatoms. The nitrogen and sulfurheteroatoms may optionally be oxidized. Such heteroaryl groups can havea single ring (e.g., pyridyl or furyl) or multiple condensed ringsprovided that the point of attachment is through a heteroaryl ring atom.Preferred heteroaryls include pyridyl, piridazinyl, pyrimidinyl,pyrazinyl, triazinyl, pyrrolyl, indolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, furanyl, thiophenyl, pyrrolyl, imidazolyl,oxazolyl, isoxazolyl, isothiazolyl, pyrazolyl, benzofuranyl,dihydrobenzofuranyl and benzothiophenyl. Heteroaryl rings may beunsubstituted or substituted by one or more moieties as described foraryl above.

“Heterocyclyl,” “heterocyclic” or “heterocyclo” refer to fully saturatedor unsaturated, cyclic groups, for example, 3 to 8 membered monocyclicor 4 to 7 membered monocyclic; 7 to 11 membered bicyclic, or 10 to 15membered tricyclic ring systems, which have one or more oxygen, sulfuror nitrogen heteroatoms in ring, preferably 1 to 4 or 1 to 3heteroatoms. The nitrogen and sulfur heteroatoms may optionally beoxidized and the nitrogen heteroatoms may optionally be quaternized. Theheterocyclic group may be attached at any heteroatom or carbon atom ofthe ring or ring system and may be unsubstituted or substituted by oneor more moieties as described for aryl groups above.

Exemplary monocyclic heterocyclic groups include, but are not limitedto, pyrrolidinyl, pyrrolyl, pyrazolyl, oxetanyl, pyrazolinyl,imidazolyl, imidazolinyl, imidazolidinyl, oxazolyl, oxazolidinyl,isoxazolinyl, isoxazolyl, thiazolyl, thiadiazolyl, thiazolidinyl,isothiazolyl, isothiazolidinyl, furyl, tetrahydrofuranyl, thienyl,oxadiazolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl,4-piperidonyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl,tetrahydropyranyl, morpholinyl, thiamorpholinyl, thiamorpholinylsulfoxide, thiamorpholinyl sulfone, 1,3-dioxolane andtetrahydro-1,1-dioxothienyl, triazolyl, triazinyl, and the like.

Exemplary bicyclic heterocyclic groups include, but are not limited to,indolyl, isoindolyl, benzothiazolyl, benzoxazolyl, benz[d]isoxazolyl,benzotriazolyl, benzodioxolyl, benzothienyl, quinuclidinyl,quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, benzimidazolyl,benzopyranyl, indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl,coumarinyl, cinnolinyl, indazolyl, pyrrolopyridyl, phthalazinyl,1,2,3-benzotriazinyl, 1,2,4-benzotriazinyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl, dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl), tetrahydroquinolinyl,tetrahydroisoquinolinyl, and the like.

Exemplary tricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, acridinyl, phenanthridinyl, xanthenyl, and the like.

Halogen means the atoms fluorine, chlorine, bromine and iodine. Thedesignation of “halo” (e.g. as illustrated in the term haloalkyl) refersto all degrees of substitutions from a single substitution to a perhalosubstitution (e.g. as illustrated with methyl as chloromethyl (—CH₂Cl),dichloromethyl (—CHCl₂), trichloromethyl (—CCl₃)).

Anthelmintic Compounds of the Invention

In a first aspect of the invention, an anthelmintic compound of Formula(I) is provided

wherein:

Y and Z are independently a bicyclic carbocyclic or a bicyclicheterocyclic group optionally substituted by one or more of halogen,nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino,aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl,haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl,alkyl- or dialkylaminocarbonyl, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl,arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl orheteroarylalkylsulfonyl; or

one of Y or Z is a bicyclic carbocyclic or a bicyclic heterocyclic groupoptionally substituted by one or more of halogen, nitro, cyano, hydroxy,hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkylcarbonyl, haloalkylcarbonyl,alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl, alkyl- ordialkylaminocarbonyl, alkylthio, halothio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy,arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl,arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl, heteroaryloxy,heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl orheteroarylalkylsulfonyl; and the other of Y or Z is alkyl, alkenyl,alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl;

wherein the alkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyland heteroaryl groups are optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino,alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylcarbonyl,haloalkylcarbonyl, alkoxycarbonyl, haloalkoxycarbonyl, aminocarbonyl,alkyl- or dialkylaminocarbonyl, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl,arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl andheteroarylalkylsulfonyl;

X₁ is a bond, —O—, —C(O)—, —C(S)—, —NH—, —S, —S(O), —S(O)₂—, —NHS(O)—,—S(O)—NH—, —NHSO₂—, —SO₂NH—, —(CH₂)_(n)— where n is 1 to 3, —C(O)—CH₂—,—CH₂—C(O)—, —O—CH₂—, —CH₂—O—, —NHCH₂—, —CH₂—NH—, —S—CH₂—, —CH₂—S—,—S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, or —CH₂—S(O)₂—, wherein each —NH—,—NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH—, —(CH₂)_(n), —C(O)CH₂—,—CH₂—C(O)—, —O—CH₂—, —CH₂—O, —NH—CH₂, —CH₂—NH—, —S—CH₂—, —CH₂—S—,—S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂— and —CH₂—S(O)₂— are optionallysubstituted with oxo (═O) or one or more halogen, cyano, hydroxy,hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl,haloalkyl, cycloalkyl or aryl groups;

X₂ is a linker selected from a C₁-C₈-alkylene group, a C₂-C₈-alkenylenegroup, a C₂-C₈-alkynylene group, a 3-8 membered carbocyclylene and 3-8membered heterocyclylene group, wherein the 3-8 membered heterocyclylenegroup contains one to four nitrogen, oxygen or sulfur atoms, and whereinone to three of the carbon atoms in the C₁-C₈-alkylene group, theC₂-C₈-alkenylene group and the C₂-C₈-alkynylene group may be replaced bya nitrogen, an oxygen or sulfur atom; and wherein the C₁-C₈-alkylenegroup, the C₂-C₈-alkenylene group, the C₂-C₈-alkynylene group, the 3-8membered carbocyclylene and the 3-8 membered heterocyclylene group areoptionally substituted with one or more substituents independentlyselected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio,haloalkylthio, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino,aminoalkyl, and oxo (═O);

X₃ is a diradical group selected from the group consisting of a bond,—(CH₂)_(n)— where n is 1 to 3, —O—, —C(S)—, —C(O)—, —S(O)—, —S(O)₂—, andan oxetane group (4-membered ring containing one oxygen), wherein X₂ andX₄ may be bonded to any carbon atom of the oxetane group; and whereineach —CH₂— in the —(CH₂)_(n)— group is optionally substituted with oneor two substituents independently selected from the group consisting ofhalogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino,aminoalkyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, carbocyclyl and halocarbocyclyl;

X₄ is a bond, —(CH₂)_(n)— where n is 1 to 3, carbocyclylene orheterocyclylene, wherein the —CH₂—, the carbocyclylene and theheterocyclylene groups are optionally substituted with one or moresubstituents independently selected from the group consisting ofhalogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino,aminoalkyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, carbocyclyl and halocarbocyclyl;

X₅ is absent or is a bond, —(CH₂)_(n) where n is 1 to 3, carbocyclyleneor heterocyclylene, wherein each —CH₂— in the —(CH₂)_(n) group, thecarbocyclylene and the heterocyclylene groups are optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, hydroxy, hydroxyalkyl, amino, alkylamino,dialkylamino, aminoalkyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, carbocyclyl and halocarbocyclyl;

X₆ is —(CH₂)_(n)— where n is 1 to 3, —O—, —C(O)—, —C(S)—, —S—, —S(O)—,—S(O)₂—, —NH—, —C(O)—NH—, —C(S)—NH—, —NH—C(O)—, —NH—C(S)—, wherein each—CH₂— in the —(CH₂)_(n)— group, —NH—, —C(O)—NH—, —C(S)—NH—, —NH—C(O)—,—NH—C(S)— are optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl,halocarbocyclyl, carbocyclylalkyl and halocarbocyclylalkyl;

X₇ is a bond, —(CH₂)_(n)— where n is 1 to 3, alkenylene, alkynylene,carbocyclylene or heterocyclylene, wherein each CH₂ in —(CH₂)_(n)—,alkenylene, alkynylene, carbocyclylene and heterocyclylene is optionallysubstituted with one or more halogen, hydroxy, hydroxyalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino oraminoalkyl group; and

X₈ is a bond, —(CH₂)_(n) where n is 1 to 3, —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—, wherein each CH₂in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH— isoptionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, alkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxyalkyl, carbocyclyl,halocarbocyclyl, carbocyclylalkyl and halocarbocyclylalkyl.

In one embodiment, at least one of Y or Z is an optionally substitutedbicyclic carbocyclic group. In another embodiment, at least one of Y orZ is an optionally substituted bicyclic aromatic carbocyclic group. Instill another embodiment, at least one of Y or Z is an optionallysubstituted non-aromatic bicyclic carbocyclic group. In still anotherembodiment, at least one of Y or Z is optionally substituted naphthyl,tetrahydronaphthyl or indanyl.

In another embodiment, at least one of Y or Z is a bicyclic heterocyclicgroup. In another embodiment, at least one of Y or Z is an optionallysubstituted bicyclic heteroaryl group. In still another embodiment, atleast one of Y or Z is optionally substituted indolyl, benzothiazolyl,benzoxazolyl, benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetra-hydroisoquinolinyl,benzimidazolyl, benzopyranyl, indolizinyl, benzofuranyl,dihydrobenzofuranyl, chromonyl, coumarinyl, benzopyranyl, cinnolinyl,quinoxalinyl, indazolyl, pyrrolopyridyl, furopyridinyl (such asfuro[2,3-c]pyridinyl, furo[3,2-b]pyridinyl] or furo[2,3-b]pyridinyl),dihydroisoindolyl or dihydroquinazolinyl (such as3,4-dihydro-4-oxo-quinazolinyl).

In one embodiment, X₁ is a bond, —C(O)—, —CH₂—, —CH₂CH₂—, —C(O)—CH₂—,—CH₂—C(O), —O—CH₂—, —CH₂—O—, —NHCH₂— or —CH₂—NH—, wherein each —CH₂—,—CH₂CH₂—, —C(O)CH₂—, —CH₂—C(O)—, —O—CH₂—, —CH₂—O, —NH—CH₂, —CH₂—NH— areoptionally substituted with one or more halogen, alkyl, haloalkyl orcycloalkyl groups.

In another embodiment, X₁ is NH—, —NHS(O)—, —S(O)—NH—, —NHSO₂— or—SO₂NH—.

In another embodiment, X₁ is a bond, —CH₂— or —CH₂CH₂—, wherein each—CH₂— or —CH₂CH₂— is optionally substituted with one or more halogen,alkyl or haloalkyl groups.

In one embodiment, X₂ is a C₁-C₈alkylene group, a 3-8 memberedcarbocyclylene or a 3-8 membered heterocyclylene group containing one tofour nitrogen, oxygen or sulfur heteroatoms, wherein one or more of thecarbon atoms in the C₁-C₈-alkylene group may be replaced by a nitrogen,oxygen or sulfur atom; and wherein the C₁-C₈-alkylene group, the 3-8membered carbocyclylene and the 3-8 membered heterocyclylene group areoptionally substituted with one or more substituents independentlyselected from halogen, alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxy,hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl and oxo (═O).

In one preferred embodiment, X₂ is —C(═O)— or optionally substitutedC₁-C₃-alkylene.

In another embodiment, X₂ comprises a chain of from 3 to 6 atoms (as anacyclic chain or part of a ring) that bridges X₁ to X₃, wherein 1 or 2of the chain atoms are nitrogen. In this embodiment, the nitrogen atomsin X₂ are typically bonded to X₁ and/or X₃.

In yet another embodiment, X₂ comprises a chain of from 3 to 6 atoms (asan acyclic chain or as part of a ring) that bridges X₁ to X₃, wherein 1or 2 of the chain atoms are nitrogen and wherein one or more of thealkylene groups in the chain are substituted with oxo (═O).

In another embodiment, X₂ is a 3-8 membered heterocyclylene groupcontaining at least one nitrogen atom. In still another embodiment, X₂is a heterocyclylene group containing at least two nitrogen atoms. Inyet another embodiment, X₂ is a 5- or 6-membered heterocyclylene groupcontaining one or two nitrogen atoms.

In certain preferred embodiments, X₂ and/or X₇ are selected from one ofthe linkers L1 to L18 in Table 1 below, wherein variables R and R′ areeach independently hydrogen, alkyl, haloalkyl or arylalkyl; R₂ and R₃are independently hydrogen, halogen, cyano, alkyl, haloalkyl orcarbocyclyl; R₄ is H, OH, halogen or C₁₋₃alkyl; R₅, R₆, R₇ and R₈ areindependently hydrogen, C₁₋₃alkyl or C₁₋₃haloalkyl; W and W′ are eachindependently O or S; and each linker L1 to L18 in the table may besubstituted by one or more of halogen, cyano, C₁-C₆alkyl, hydroxy,thiol, C₁-C₆alkoxy, oxo or thiocarbonyl.

TABLE 1 Examples of X₂ and X₇ Linkers

L1

L2

L3

L4

L5

L6

L7

L8

L9

L10

L11

L12

L13

L14

L15

L16

L17

L18

It will be understood that the X₂ and X₇ linkers presented in Table 1may be bonded to X₁ and/or X₃ or X₆ and/or X₈ at any possible atom inthe linker group. Typically, when the X₂ and/or the X₇ linker containsone or more nitrogen atoms, the nitrogen atom(s) will be bonded to X₁and/or X₃ or X₆ and/or X₇.

In one embodiment, X₂ and/or X₇ is L1. In another preferred embodiment,X₂ and/or X₇ is L2. In yet another preferred embodiment, X₂ and/or X₇ isL11 or L12. In another embodiment, X₂ and/or X₇ is L13 or L14. In stillanother embodiment, X₂ and/or X₇ is L13 where the R₆ and R₇ groups arein a trans relationship to each other. In yet another embodiment, X₂and/or X₇ are L13 where the R₆ and R₇ groups are in a cis-relationshipto each other. In another embodiment, X₂ and/or X₇ are L14 where the R₆and R₇ groups are in a trans-relationship to each other. In stillanother embodiment, X₂ and/or X₇ are L14 where the R₆ and R₇ are in acis-relationship to each other. In yet another embodiment, X₂ and/or X₇are L15 where the R₆ and R₇ are trans to each other. In still anotherembodiment, X₂ and/or X₇ are L15 where R₆ and R₇ are cis- to each other.In still another embodiment, X₂ and/or X₇ are L16, L17 or L18.

In certain embodiments, X₃ is a bond, —(CH₂)_(n)— where n is 1 to 3,—C(S)— or —C(O)—, wherein each carbon atom in the —(CH₂)_(n)— group isoptionally substituted with one or two substituents independentlyselected from the group consisting of halogen, alkyl or haloalkyl. Inone preferred embodiment, X₃ is C(O)—. In another preferred embodiment,X₃ is CH₂CH₂— or —CH₂CH₂CH₂— wherein each of the carbon atoms may besubstituted by one or two methyl groups. In yet another embodiment, X₃is an oxetane group.

In one embodiment, X₄ is a bond. In another embodiment, X₄ is—(CH₂)_(n)— where n is 1 or 2, wherein each —CH₂— is optionallyindependently substituted with one or two substituents selected from thegroup consisting of halogen, alkyl, haloalkyl and carbocyclyl;

In another embodiment, X₅ is a bond or —(CH₂)_(n)— where n is 1 or 2 andwherein each —CH₂— in the —(CH₂)_(n) group is optionally independentlysubstituted with one or two halogen, alkyl, haloalkyl, or carbocyclylgroups;

In yet another embodiment of formula (I), X₆ is —(CH₂)_(n) where n is 1or 2, —O—, —C(O)—, —S—, —S(O)—, —S(O)₂— or —NH—, wherein each —CH₂— inthe —(CH₂)_(n)— group or the NH, is optionally independently substitutedwith one or two substituents is selected from the group consisting ofhalogen, alkyl, haloalkyl and carbocyclyl. In one preferred embodiment,X₆ is CH₂. In another preferred embodiment, X₆ is —O—.

In another embodiment of formula (I), X₇ is a bond, —(CH₂)_(n)— where nis 1 to 3, carbocyclylene or heterocyclylene, wherein each CH₂ in—(CH₂)_(n)—, carbocyclylene and heterocyclylene is optionallysubstituted with one or more halogen, alkyl, haloalkyl, hydroxy,hydroxyalkyl, alkoxy, haloalkoxy, amino, alkylamino or dialkylamino oraminoalkyl. In another embodiment, X₇ is a 5- or 6-memberedcarbocyclylene group such as cyclohexylene or cyclopentylene. In yetanother embodiment, X₇ is a phenylene group.

In yet another embodiment of formula (I), X₈ is absent or is a bond,—(CH₂)_(n) where n is 1 to 3, —O—, —C(O)— or —NH—, wherein each CH₂ in—(CH₂)_(n)— and the —NH— is optionally independently substituted withone or two substituents selected from the group consisting of halogen,alkyl, and haloalkyl. In one particularly preferred embodiment, X₈ isNH—. In another embodiment, X₈ is —C(O)—. In yet another preferredembodiment, X₈ is —CH₂—, —CF₂—, —CH(CH₃)— or C(CH₃)₂—. In still anotherembodiment, X₈ is —NHS(O)—, —S(O)—NH—, —NHSO₂— or —SO₂NH—.

In one aspect of the invention, the compounds of formula (I) have thestructure (IA) shown below:

Wherein variables Y, X₁, X₈ and Z are as defined for formula (I) above,Ring A and Ring B are independently a 3 to 8-membered monocyclic or a 7to 11-membered bicyclic carbocyclylene or heterocyclylene ring, whereinthe heterocyclic ring contains 1 to 4 heteroatoms selected from N, O andS; and the Linker is the segment —X₃—X₄—X₅—X₆— where X₃, X₄, X₅ and X₆are as defined for formula (I).

In one embodiment of formula (IA), Ring A is one of L1 to L10; or L13 toL18 as defined in Table 1, which may optionally be substituted withhalogen, alkyl or haloalkyl. In another embodiment, Ring A iscyclohexylene or phenylene, which may optionally be substituted withhalogen, alkyl or haloalkyl. In another embodiment of formula (IA), RingB is cyclohexylene or phenylene, which may optionally be substitutedwith halogen, alkyl or haloalkyl. In still another embodiment, Ring B isone of L1 to L10; or L13 to L18 as defined in Table 1, which mayoptionally be substituted with halogen, alkyl or haloalkyl.

In one embodiment of formula (IA), X₁ is a bond, an optionallysubstituted —(CH₂)_(n)— where n is 1 to 3, or —C(O)—.

In another embodiment of formula (IA), X₈ is —C(O)—, —NH— or —(CH₂)_(n)—where n is 1 to 3, wherein the each CH₂ in (CH₂)_(n)— or the NH— mayoptionally be substituted.

In still another embodiment of formula (IA), Y and/or Z is phenyl ornaphthyl optionally substituted with one or more of halogen, nitro,cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino,aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio,arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl,heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio,heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio,heteroarylalkylsulfinyl or heteroarylalkylsulfonyl, with the provisothat at least one or Y or Z is naphthyl.

In yet another embodiment of formula (IA), Y and/or Z are independentlyphenyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more halogen, nitro, cyano, hydroxy,hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl,arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl orheteroarylalkylsulfonyl, with the proviso that at least one of Y or Z isa bicyclic ring.

In certain embodiments of formula (IA), the compound has the structureof formula (IA-1) or (IA-2) shown below:

wherein variables Y, X₆, X₈ and Z are as defined for formula (I) above;X₁ is a bond, —C(O)—, —C(S)—, —NH—, —S(O)—, —S(O)₂—, —NHS(O)—,—S(O)—NH—, —NHSO₂—, —SO₂NH—, —(CH₂)_(n)— where n is 1 to 3, —O—CH₂—,—NHCH₂—, —S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, and —CH₂—S(O)₂—,wherein each —NH—, —(CH₂)_(n)—, —O—CH₂—, —NHCH₂—, —S—CH₂—, —S(O)—CH₂—,—CH₂—S(O)—, —S(O)₂—CH₂—, and —CH₂—S(O)₂— are optionally substituted withoxo (═O) or one or more halogen, cyano, alkyl, haloalkyl, cycloalkyl oraryl groups; Ring A is a 3- to 8-membered carbocyclic ring where Q5 andQ6 are independently N or CR₄ where R₄ is H, OH, halogen or C₁₋₃alkyl; Wis O, S or an oxetane group (—CH₂OCH₂—); Q₁, Q₂, Q₃ and Q₄ are eachindependently C—H or a heteroatom selected from N, S or O; each R₁ isindependently halogen, cyano, hydroxyl, amino, alkylamino, dialkylamino,alkyl, haloalkyl, carbocyclyl, heterocyclyl, alkenyl, haloalkenyl,alkynyl or haloalkynyl; R₂ and R₃ are independently hydrogen, halogen,cyano, alkyl, haloalkyl or carbocyclyl; n is 0, 1, 2 or 3; m is 0, 1, 2,3 or 4; and r is 0 to 5.

In one embodiment of formula (IA-1), W is O. In another embodiment, W isan oxetane group. In another embodiment, Ring B is optionallysubstituted phenylene.

In another embodiment of formula (IA-1) or (IA-2), Ring A is one oflinkers L1, L2, L3, L8, L13, L14, L15, L16, L17 or L18. In anotherembodiment, Ring A is one of L1, L13, L14 or L15. In yet anotherembodiment, Ring A is L16, L17 or L18. In another embodiment, Ring A isL4, L5, L6, L7, L9 or L10. In another embodiment, Ring B is L1, L13, L14or L15. In still another embodiment of formula (IA-1), Y and/or Z isnaphthyl optionally substituted by one or more of halogen, nitro, cyano,alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In yet another embodiment of formula (IA-1), Y and/or Z areindependently benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more of halogen, nitro, cyano,alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In another embodiment of formula (IA-1), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl andthe other of Y or Z is phenyl, a 3-8 membered heterocyclyl group or a 5or 6-membered heteroaryl group, each of which is optionally substitutedby one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl,hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl,alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In still another embodiment of formula (IA-1), one of Y or Z isnaphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl andthe other of Y or Z is phenyl or a 5- or 6-membered heteroaryl group,each of which is optionally substituted by one or more of halogen,nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino,alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio,halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonylor haloalkylsulfonyl.

In another embodiment, one of Y or Z is naphthyl, benzofuranyl,dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl,benzimidazolyl, or benzothiazolyl, each of which is optionallysubstituted by one or more of chloro, fluoro, bromo, CF₃, OCF₃, SCF₃ orSF₅; and the other of Y or Z is phenyl optionally substituted by cyano,nitro, CF₃, SF₅, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl, S(O)C₁₋₃haloalkyl orS(O)₂C₁₋₃haloalkyl.

In another embodiment of formula (IA-1), Y and Z are independentlyphenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more of halogen, nitro, cyano,C₁₋₃alkyl, C₁₋₃haloalkyl, phenyl, hydroxy, C₁₋₃hydroxyalkyl, amino,C₁₋₃alkyl- or C₁₋₃dialkylamino, C₁₋₃alkoxy, C₁₋₃haloalkoxy, halothio,C₁₋₃haloalkylthio, C₁₋₃ alkylsulfinyl C₁₋₃alkylsulfonyl orC₁₋₃haloalkylsulfonyl, with the proviso that at least one of Y and Z isa bicyclic ring;

Ring A is one of L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15,L16, L17 or L18 shown in Table 1;

X₁ is a bond, —C(O)—, —(CH₂)_(n)— where n is 1 to 3, —O—CH₂—, —NHCH₂—,—S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, and —CH₂—S(O)₂—, whereineach —(CH₂)_(n)—, —O—CH₂—, —NHCH₂—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—,and —CH₂—S(O)₂— are optionally substituted with oxo (═O) or one or morehalogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups;

W is O, S or an oxetane group;

each R₁ is independently halogen, cyano, hydroxyl, amino,C₁₋₃alkylamino, C₁₋₃ dialkylamino, C₁₋₃alkyl or C₁₋₃haloalkyl;

R₂ and R₃ are independently H, halogen, C₁-C₃alkyl or C₁-C₃haloalkyl;

X₆ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O—, —NH—, —C(O)—NH— and—NH—C(O)—, wherein each —CH₂— in the —(CH₂)_(n)— group, —NH—, —C(O)—NH—and —NH—C(O)— are optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₃hydroxyalkyl, amino, C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃aminoalkyl, C₁₋₃alkyl and C₁₋₃haloalkyl;

X₈ is a bond, —(CH₂)_(n) where n is 1 to 3, —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—, wherein each CH₂in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH— isoptionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃hydroxyalkyl, C₁₋₃aminoalkyl,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃ alkoxyalkyl;

Q₁, Q₂, Q₃ and Q₄ are each independently C—H or a heteroatom selectedfrom N, S or O;

the dashed lines represent a single or double bond;

n is 0, 1, 2 or 3; and m is 0, 1, 2, 3 or 4. In another embodiment offormula (IA-1), one of Y or Z is naphthyl, benzofuranyl,dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl,benzimidazolyl, or benzothiazolyl, each of which is optionallysubstituted by one or more of chloro, fluoro, bromo, CF₃, OCF₃, SCF₃ orSF₅; and the other of Y or Z is phenyl optionally substituted by cyano,nitro, CF₃, SF₅, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl, S(O)C₁₋₃haloalkyl orS(O)₂C₁₋₃haloalkyl;

Ring A is one of L1, L2, L3, L4, L5, L13, L14, L15, L16, L17 or L18;Ring B is trans-cyclohexylene or phenylene;

W is O;

X₆ is a bond, —O—, —(CH₂)_(n)— where n is 1 to 3 or —NH—;

X₈ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O— or —NH—, wherein eachCH₂ in —(CH₂)_(n)— and —NH— is optionally independently substituted withone or two substituents selected from the group consisting of halogen,C₁₋₃alkyl or C₁₋₃haloalkyl;

R₂ and R₃ are H; n is 1 or 2; and m is 0.

In another embodiment, X₁ is optionally substituted —(CH₂)_(n)— or—C(O)—. In another embodiment, X₈ is —C(O)— or optionally substituted—NH— or —(CH₂)_(n)—. In still another embodiment of formula (IA-1), R₂and R₃ are H. In still another embodiment of formula (IA-1), n is 1 or2. In another embodiment of formula (IA-1), X₆ is —O—, —NH— which mayoptionally be substituted by alkyl or haloalkyl; —S—, —S(O)— or —S(O)₂—.In yet another embodiment of formula (IA-1), X₁ is a bond, —C(O)— or—CH₂—; W is O, X₆ is —O—, n is 0, 1 or 2, R₂ and R₃ are H and m is 0.

In one embodiment of formula (IA-1), Q₁ is N. In another embodiment, Q₂is N. In another embodiment, Q₃ is N. In yet another embodiment, Q₄ isN.

In one embodiment, Q₁ and Q₄ are N. In another embodiment, Q₂ and Q₃ areN. In still another embodiment, Q₁ and Q₂ are N. In another embodiment,Q₃ and Q₄ are N.

In another embodiment, Q₁ and Q₃ are N. In still another embodiment, Q₂and Q₄ are N.

In an embodiment, Q₅ is N and Q₆ is CH. In another embodiment, Q₅ is CHand Q₆ is N. In yet another embodiment, Q₅ and Q₆ are both N. In stillanother embodiment, Q₅ and Q₆ are both CH.

In another embodiment of formula (IA-1), Ring A is one of L1, L2, L3,L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17 or L18; Ring B is aoptionally substituted cyclohexylene or phenylene, Y and/or Z areindependently phenyl, naphthyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl,dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl,with the proviso that at least one of Y or Z is a bicyclic ring; X₁ isbond, —C(O)— or —CH₂—; W is O or an oxetane group, X₆ is —O—, n is 0, 1or 2, R₂ and R₃ are H, m is 0 and X₈ is —NH—, —C(O)—, —CH₂—, —CF₂—,—CH(CH₃)— or —C(CH₃)₂—.

In another embodiment of formula (IA-1), Ring A is one of L1, L4, L13,L14, L15 or L16; Ring B is an optionally substituted diradical pyridinering linker where one of Q₁, Q₂, Q₃ or Q₄ is N, Y and/or Z areindependently phenyl, naphthyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl,dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl,with the proviso that at least one of Y or Z is a bicyclic ring; X₁ isbond, —C(O)— or —CH₂—; W is O or an oxetane group, X₆ is —O—, n is 0, 1or 2, R₂ and R₃ are H, m is 0 and X₈ is —NH—, —C(O)—, —CH₂—, —CF₂—,—CH(CH₃)— or —C(CH₃)₂—.

In another embodiment of formula (IA-1), Ring A is L1, L2, L3, L4, L5,L6, L7, L8, L13, L14, L15, L16, L17 or L18; Ring B is a optionallysubstituted cyclohexylene or phenylene, Y and/or Z are independentlyphenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolylor benzothiazolyl, each of which is optionally substituted by one ormore of halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl,amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy,alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl or haloalkylsulfonyl, with the proviso that one of Y or Zis a bicyclic ring; X₁ is bond, —C(O)— or —CH₂—; W is O, X₆ is —O—, n is1 or 2, R₂ and R₃ are H, m is 0 and X₈ is —NH—, —C(O)—, —CH₂—, —CF₂—,—CH(CH₃)— or —C(CH₃)₂—.

In other embodiments of formula (IA-1), the invention provides thecompounds in Table 2 below:

TABLE 2 Compounds of formula (IA-1) where R₁ is not present; OX. =oxetane group; B = bond Ring Y X₁ A W n R₂ R₃ X₆ Ring B X₈ Z #

B L1 O 1 H H O trans- C₆H₁₀ NH

14

B L1 O 1 H H O trans- C₆H₁₀ NH

17

B L1 O 1 H H O trans- C₆H₁₀ NH

20

B L1 O 1 H H O trans- C₆H₁₀ NH

88

B L1 O 1 H H O trans- C₆H₁₀ NH

89

B L1 O 1 H H O trans- C₆H₁₀ NH

90

B L1 O 1 H H O trans- C₆H₁₀ NH

97

B L1 O 1 H H O trans- C₆H₁₀ NH

98

B L1 O 1 H H O trans- C₆H₁₀ NH

99

B L1 O 1 H H O trans- C₆H₁₀ NH

160

B L1 O 1 H H O trans- C₆H₁₀ NH

161

B L1 O 1 H H O trans- C₆H₁₀ NH

232

B L1 O 1 H H O trans- C₆H₁₀ NH

233

B L1 O 1 H H O trans- C₆H₁₀ NH

236

B L1 O 1 H H O trans- C₆H₁₀ NH

237

B L1 O 1 H H O trans- C₆H₁₀ NMe

245

B L1 O 1 H H O trans- C₆H₁₀ NMe

246

B L1 O 1 H H O trans- C₆H₁₀ NMe

247

B L1 O 1 H H O trans- C₆H₁₀ NMe

248

B L1 O 1 H H O trans- C₆H₁₀ NH

249

B L1 O 1 H Me O trans- C₆H₁₀ NH

250

B L1 O 1 H Me O trans- C₆H₁₀ NH

251

B L1 O 1 H Me O trans- C₆H₁₀ NH

252

B L1 S 1 H H O trans- C₆H₁₀ NH

263

B L1 S 1 H H O trans- C₆H₁₀ NH

264

B L1 O 1 H H O trans- C₆H₁₀ NH

266

B L1 O 1 H H O trans- C₆H₁₀ NH

267

B L1 O 1 H H O trans- C₆H₁₀ NH

268

B L1 O 1 H H O trans- C₆H₁₀ NMe

269

B L1 O 1 H H O trans- C₆H₁₀ NH

270

B L1 O 1 H H O trans- C₆H₁₀ NH

271

B L1 O 1 H H O trans- C₆H₁₀ NH

272

B L1 O 1 H H O trans- C₆H₁₀ NH

273

B L1 O 1 H H O trans- C₆H₁₀ NH

277

B L1 O 1 H H O trans- C₆H₁₀ NH

278

B L1 O 1 H H O trans- C₆H₁₀ NH

279

B L1 O 1 H H O trans- C₆H₁₀ NMe

281

B L1 O 1 H H O trans- C₆H₁₀ NMe

282

B L1 O 1 H H O trans- C₆H₁₀ NMe

283

B L1 O 1 H H O trans- C₆H₁₀ NH

289

B L1 O 1 H H O trans- C₆H₁₀ NH

290

B L1 O 1 H H O trans- C₆H₁₀ NMe

293

B L1 O 1 H H O trans- C₆H₁₀ NH

314

B L1 O 1 H H O trans- C₆H₁₀ NH

331

B L1 O 1 H H O trans- C₆H₁₀ NH

335

B L1 O 1 H H O trans- C₆H₁₀ NH

336

B L1 O 1 H H O trans- C₆H₁₀ NH

342

B L1 O 1 H H O trans- C₆H₁₀ NH

358

B L1 O 1 H H O trans- C₆H₁₀ NH

364

B L1 O 1 F F O trans- C₆H₁₀ NH

390

B L1 O 1 H H O trans- C₆H₁₀ NH

399

B L1 O 1 H H O trans- C₆H₁₀ NH

400

B L1 O 1 H H O trans- C₆H₁₀ NH—SO₂

402

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH—SO₂

403

B L1 O 1 H H O trans- C₆H₁₀ NH—SO₂

404

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH—SO₂

405

CH₂ L1 O 1 H H O C₆H₄ CH₂

132

CH₂ L1 O 1 H H O C₆H₄ CH₂

133

CH₂ L1 O 1 H H O C₆H₄ CO

134

CH₂ L1 O 1 H H O C₆H₄ CO

135

CH₂ L1 O 1 H H O C₆H₄

136

CH₂ L1 O 1 H H O C₆H₄

137

CH₂ L1 O 1 H H O C₆H₄

138

CH₂ L1 O 1 H H O C₆H₄

139

CH₂ L1 O 1 H H O C₆H₄

140

CH₂ L1 O 1 H H O C₆H₄

141

CH₂ L1 O 1 H H O C₆H₄ CF₂

142

CH₂ L1 O 1 H H O C₆H₄ CF₂

143

B L1 O 1 H H O

NH

144

B L1 O 1 H H O

NH

145

CH₂ L1 O 1 H H O

NH

146

CH₂ L1 O 1 H H O

NH

147

B L1 O 1 H H O

O

152

B L1 O 1 H H O

O

153

B L1 O 1 H H O

O

154

CH₂ L1 O 1 H H O

O

155

B L1 O 1 H H bond

NH

148

CH₂ L1 O 1 H H bond

NH

149

B L1 O 1 H H bond

NH

150

B L1 O 1 H H bond

NH

151

CO L1 O 1 H H bond

O

156

B L1 O 1 H H bond

O

157

B L1 O 1 H H bond

O

158

B L1 O 1 H H bond

O

159

CH₂ L1 O 1 H H O C₆H₄ NH

68

CH₂ L1 O 1 H H O C₆H₄ NH

184

CH₂ L1 O 1 H H O C₆H₄ NH

185

CH₂ L1 O 1 H H O C₆H₄ NH

186

CH₂ L1 O 1 H H O C₆H₄ NH

187

CH₂ L1 O 1 H H O C₆H₄ NH

188

O L1 O 1 H H O C₆H₄ NH

189

CO L1 O 1 H H O C₆H₄ NH

190

CO L1 O 1 H H O C₆H₄ NH

191

B L1 O 1 H H O trans- C₆H₁₀ B

409

B L1 O 1 H H O trans- C₆H₁₀ B

410

B L1 O 1 H H O trans- C₆H₁₀ B

411

B L1 O 1 H H O trans- C₆H₁₀ B

412

B L1 O 1 H H O trans- C₆H₁₀ B

413

B L1 O 1 H H O trans- C₆H₁₀ B

414

B L1 OX 1 H H O trans- C₆H₁₀ —NH—

415

CH₂ L1 OX 1 H H O trans- C₆H₁₀ —NH—

416

B L1 O 0 — — —NH— trans- C₆H₁₀ —NH—

395

B L1 O 0 — — —NMe— trans- C₆H₁₀ —NH—

397

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

24

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

76

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

77

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

78

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

79

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

80

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

81

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

82

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

83

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

84

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

85

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

86

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

87

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

260

CH₂ L1 O 1 H H O trans- C₆H₁₀ NMe

261

L1 O 1 H H O trans- C₆H₁₀ NMe

262

CH₂ L1 S 1 H H O trans- C₆H₁₀ NH

265

CH₂ L1 O 1 H H O trans- C₆H₁₀ NMe

280

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

299

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

310

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

377

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

378

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

379

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

380

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

401

CH₂ L13 O 1 H H O trans- C₆H₁₀ NH

307

CH₂ L13 O 1 H H O trans- C₆H₁₀ NH

308

B L15 O 1 H H O trans- C₆H₁₀ NH

309

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

178

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

179

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

180

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

181

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

182

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

183

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

234

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

235

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

253

L1 O 1 H H O trans- C₆H₁₀ NH

254

L1 O 1 H H O trans- C₆H₁₀ NH

255

CH₂ L1 O 1 H H O trans- C₆H₁₀ NMe

256

L1 O 1 H H O trans- C₆H₁₀ NMe

257

CH₂ L1 O 1 H H O trans- C₆H₁₀ NMe

258

L1 O 1 H H O trans- C₆H₁₀ NMe

259

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

274

CH₂ L1 O 1 H H O trans- C₆H₁₀ NMe

275

CH₂ L1 O 1 H H O trans- C₆H₁₀ NMe

284

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

285

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

286

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

287

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

288

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

291

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

292

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

294

L1 O 1 H H O trans- C₆H₁₀ NH

300

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

301

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

302

L1 O 1 H H O trans- C₆H₁₀ NH

304

L1 O 1 H H O trans- C₆H₁₀ NH

406

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

305

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

306

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

312

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

313

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

315

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

316

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

318

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

319

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

320

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

321

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

322

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

323

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

324

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

325

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

326

L1 O 1 H H O trans- C₆H₁₀ NH

330

C(O) L1 O 1 H H O trans- C₆H₁₀ NH

338

L1 O 1 H H O trans- C₆H₁₀ NH

343

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

344

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

375

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

376

CH₂ L13 O 1 H H O trans- C₆H₁₀ NH

365

CH₂ L13 O 1 H H O trans- C₆H₁₀ NH

370

CH₂ L14 O 1 H H O trans- C₆H₁₀ NH

371

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

311

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

297

L1 O 1 H H O trans- C₆H₁₀ NH

298

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

327

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

328

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

329

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

332

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

333

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

334

CH₂ L13 O 1 H H O trans- C₆H₁₀ NH

357

CH₂ L14 O 1 H H O trans- C₆H₁₀ NH

372

CH₂ L13 O 1 H H O trans- C₆H₁₀ NH

373

CH₂ L14 O 1 H H O trans- C₆H₁₀ NH

374

B L1 O 1 H H O trans- C₆H₁₀ NH

391

B L1 O 1 H H O trans- C₆H₁₀ NH

392

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

393

B L1 O 1 H H O trans- C₆H₁₀ NH

394

B L16 O 1 H H O trans- C₆H₁₀ NH

407

CH₂ L16 O 1 H H O trans- C₆H₁₀ NH

408

B L1 O 1 H H O trans- C₆H₁₀ NH

417

B L1 O 1 H H O trans- C₆H₁₀ NH

418

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

419

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

420

B L1 O 1 H H O trans- C₆H₁₀ NH

421

B L1 O 1 H H O trans- C₆H₁₀ NH

422

B L1 O 1 H H O trans- C₆H₁₀ NH

423

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

424

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

425

CH₂ L1 O 1 H H O trans- C₆H₁₀ NH

426

B L15 O 1 H H O trans- C₆H₁₀ NH

427

In one embodiment of formula (IA-2), W is O. In another embodiment, W isan oxetane group.

In another embodiment of formula (IA-2), Ring A is one of linkers L1,L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14, L15, L16, L17 or L18. Inanother embodiment, Ring A is one of L1, L2, L3, L8, L13, L14, L15, L16,L17 or L18. In another embodiment, Ring A is L1, L13, L14 or L15. In yetanother embodiment, Ring A is L16, L17 or L18.

In still another embodiment of formula (IA-2), Y and/or Z is naphthyloptionally substituted with one or more of halogen, nitro, cyano, alkyl,haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In yet another embodiment of formula (IA-2), Y and/or Z areindependently benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more halogen, nitro, cyano,alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In another embodiment of formula (IA-2), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl andthe other of Y or Z is phenyl, a 3-7 membered heterocyclyl group or a 5or 6-membered heteroaryl group, each of which is optionally substitutedby one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl,hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl,alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In still another embodiment of formula (IA-2), one of Y or Z isnaphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl andthe other of Y or Z is phenyl or a 5- or 6-membered heteroaryl group,each of which is optionally substituted by one or more of halogen,nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino,alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio,halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonylor haloalkylsulfonyl.

In another embodiment, one of Y or Z is naphthyl, benzofuranyl,dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl,benzimidazolyl, or benzothiazolyl, each of which is optionallysubstituted by one or more of chloro, fluoro, bromo, CF₃, OCF₃, SCF₃ orSF₅; and the other of Y or Z is phenyl optionally substituted by cyano,nitro, CF₃, SF₅, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl, S(O)C₁₋₃haloalkyl orS(O)₂C₁₋₃haloalkyl.

In another embodiment of formula (IA-2), Y and Z are independentlyphenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more of halogen, nitro, cyano,C₁₋₃alkyl, C₁₋₃haloalkyl, phenyl, hydroxy, C₁₋₃hydroxyalkyl, amino,C₁₋₃alkyl- or C₁₋₃ dialkylamino, C₁₋₃alkoxy, C₁₋₃haloalkoxy,C₁₋₃alkylthio, C₁₋₃haloalkylthio, C₁₋₃ alkylsulfinyl,C₁₋₃haloalkylsulfinyl, C₁₋₃alkylsulfonyl, C₁₋₃haloalkylsulfonyl or SF₅,with the proviso that at least one of Y and Z is a bicyclic ring;

Ring A is one of linkers L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13,L14, L15, L16, L17 or L18;

X₁ is a bond, —C(O)—, —(CH₂)_(n)— where n is 1 to 3, —O—CH₂—, —NHCH₂—,—S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, and —CH₂—S(O)₂—, whereineach —(CH₂)_(n)—, —O—CH₂—, —NHCH₂—, —S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—,—S(O)₂—CH₂—, and —CH₂—S(O)₂— are optionally substituted with oxo (═O) orone or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups;

W is O, S or an oxetane group;

each R₁ is independently halogen, cyano, hydroxyl, amino,C₁₋₃alkylamino, C₁₋₃ dialkylamino, C₁₋₃alkyl or C₁₋₃haloalkyl;

R₂ and R₃ are independently H, halogen, C₁-C₃alkyl or C₁-C₃haloalkyl;

X₈ is a bond, —(CH₂)_(n) where n is 1 to 3, —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—, wherein each CH₂in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH— isoptionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃hydroxyalkyl, C₁₋₃aminoalkyl,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃ alkoxyalkyl; n is 0, 1, 2 or 3; and ris 0, 1, 2, 3 or 4.

In another embodiment, X₁ is optionally substituted —(CH₂)_(n)— or—C(O)—. In another embodiment, X₈ is —C(O)— or optionally substitutedNH— or —(CH₂)_(n)—. In still another embodiment of formula (IA-2), R₂and R₃ are H. In still another embodiment of formula (IA-2), n is 1 or2. In yet another embodiment of formula (IA-2), X₁ is a bond, —C(O)— or—CH₂—; W is O, n is 1 or 2, R₂ and R₃ are H and r is 0. In anotherembodiment of formula (IA-2), Y and/or Z are independently naphthyl,quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl,benzofuranyl, dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl,each of which is optionally substituted with one or more halogen, nitro,cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- ordialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl orhaloalkylsulfonyl; X₁ is bond, —C(O)— or —CH₂—; W is O, n is 1 or 2, R₂and R₃ are H, r is 0 and X₈ is —NH—, —C(O)—, —CH₂—, —CF₂—, —CH(CH₃)— orC(CH₃)₂—.

In other embodiments of formula (IA-2), the invention provides thecompounds in Table 3 below:

TABLE 3 Compounds of formula (IA-2) wherein X₁ = bond, R₁ is notpresent, R₂ = H and X₈ is —NH— Y Ring A n R₃ Z Compound #

L1 2 Me

13

L1 2 Me

16

L1 2 Me

19

L1 2 Me

91

L1 2 Me

92

L1 2 Me

93

L1 2 Me

100

L1 2 Me

101

L1 2 Me

102

L1 3 H

15

L1 3 H

18

L1 3 H

21

L1 3 H

94

L1 3 H

95

L1 3 H

96

L1 3 H

103

L1 3 H

104

L1 3 H

105

In another aspect of the invention, the compounds of formula (I) havethe structure (TB) shown below:

Wherein variables Y, X₈ and Z are as defined for formula (I), Ring B isindependently a 3- to 8-membered carbocyclylene or a 3- to 8-memberedheterocyclylene ring with 1 to 3 heteroatoms selected from oxygen,sulfur and nitrogen; or a 7- to 11-membered bicyclic carbocyclylene or7- to 11-membered heterocyclylene ring containing 1 to 4 heteroatomsselected from oxygen, sulfur and nitrogen; and the Linker is the segmentX₁—X₂—X₃—X₄—X₅—X₆— where X₁, X₂, X₃, X₄, X₅ and X₆ are as defined forformula (I).

In an embodiment of formula (TB), variables X₄ and/or X₅ in the Linkersegment X₁—X₂—X₃—X₄—X₅—X₆— are absent. In another embodiment of formula(IB), Ring B is one of L1 to L10 or L13 to L18 as defined in Table 1,which may optionally be substituted with halogen, alkyl or haloalkyl. Inanother embodiment of formula (IB), Ring B is cyclohexylene orphenylene, which may optionally be substituted with halogen, alkyl orhaloalkyl.

In still another embodiment of formula (IB), Y and/or Z is naphthyloptionally substituted with one or more of halogen, nitro, cyano,hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl,alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio,arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl,heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio,heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio,heteroarylalkylsulfinyl or heteroarylalkylsulfonyl.

In yet another embodiment of formula (IB), Y and/or Z are independentlybenzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, hydroxy,hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl, haloalkylsulfonyl,aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl,arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl orheteroarylalkylsulfonyl.

In another embodiment of formula (IB), the compound has the structure offormula (IB-1), (IB-2), (IB-3), (IB-4) or (IB-5) shown below:

wherein Y, X₁, X₆, X₈ and Z are as defined above for formula (I); W andW′ are each independently O, S or oxetane; Q₁, Q₂, Q₃ and Q₄ are eachindependently C—H or a heteroatom selected from N, S or O; R and R′ areeach independently hydrogen, alkyl, haloalkyl or arylalkyl; R₁ isindependently halogen, cyano, hydroxyl, amino, alkylamino, dialkylamino,alkyl, haloalkyl, carbocyclyl, heterocyclyl, alkenyl, haloalkenyl,alkynyl or haloalkynyl; R₂ and R₃ are independently hydrogen, halogen,cyano, alkyl, haloalkyl or carbocyclyl; n is 0, 1, 2 or 3; r is 0, 1, 2,3 or 4; and the dotted lines in the ring represent single or doublebonds.

In one embodiment of formulae (IB-1), (IB-2), (IB-3) and (IB-4), Yand/or Z is naphthyl optionally substituted with one or more of halogen,nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- ordialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl orhaloalkylsulfonyl. In yet another embodiment of formulae (IB-1), (IB-2),(IB-3) and (IB-4), Y and/or Z are independently benzofuranyl,dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl,benzimidazolyl, or benzothiazolyl each of which is optionallysubstituted by one or more halogen, nitro, cyano, alkyl, haloalkyl,hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl,alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In another embodiment of formulae (IB-1), (IB-2), (IB-3) and (IB-4), oneof Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more of halogen, nitro, cyano,alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- ordialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl orhaloalkylsulfonyl and the other of Y or Z is phenyl, a 3-8 memberedheterocyclyl group or a 5 or 6-membered heteroaryl group, each of whichis optionally substituted by one or more of halogen, nitro, cyano,alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- ordialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl orhaloalkylsulfonyl.

In still another embodiment of formulae (IB-1), (IB-2), (IB-3) and(IB-4), one of Y or Z is naphthyl, benzofuranyl, dihydrobenzofuranyl,quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl,indolyl, isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl,each of which is optionally substituted by one or more of halogen,nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino,alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio,halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonylor haloalkylsulfonyl and the other of Y or Z is phenyl or a 5- or6-membered heteroaryl group, each of which is optionally substituted byone or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy,hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy,haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl. In anotherembodiment, one of Y or Z is naphthyl, benzofuranyl,dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl,benzimidazolyl, or benzothiazolyl, each of which is optionallysubstituted by one or more of chloro, fluoro, bromo, CF₃, OCF₃, SCF₃ orSF₅, and the other of Y or Z is phenyl optionally substituted by cyano,nitro, CF₃, SF₅, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl, S(O)C₁₋₃haloalkyl orS(O)₂C₁₋₃haloalkyl.

In one embodiment of formulae (IB-1), (IB-2), (IB-3) and (IB-4), Q₁ isN. In another embodiment, Q₂ is N. In another embodiment, Q₃ is N. Inyet another embodiment, Q₄ is N.

In one embodiment, Q₁ and Q₄ are N. In another embodiment, Q₂ and Q₃ areN. In still another embodiment, Q₁ and Q₂ are N. In another embodiment,Q₃ and Q₄ are N.

In another embodiment, Q₁ and Q₃ are N. In still another embodiment, Q₂and Q₄ are N.

In one embodiment of formula (IB-1), W is O. In another embodiment, W isan oxetane group. In another embodiment, the ring is an optionallysubstituted cyclohexylene group. In yet another embodiment, the ring isan optionally substituted phenylene group. In yet another embodiment, X₆is —NH— in which the hydrogen may be replaced by alkyl, haloalkyl orarylalkyl, —O—, —S—, —S(O)— or —S(O)₂—. In another embodiment, X₆ is—(CH₂)_(n)-optionally substituted by halogen, alkyl or haloalkyl. Instill another embodiment of formula (IB-1), R₂ and R₃ are H. In stillanother embodiment of formula (IB-1), n is 1 or 2. In another embodimentof formula (IB-1), X₆ is —O— or —NH— which may optionally be substitutedby alkyl or haloalkyl or arylalkyl.

In another embodiment of formula (IB-1), Y and Z are independentlyphenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more of halogen, nitro, cyano,SF₅, C₁₋₃alkyl, C₁₋₃haloalkyl, phenyl, hydroxy, C₁₋₃hydroxyalkyl, amino,C₁₋₃alkyl- or C₁₋₃dialkylamino, C₁₋₃alkoxy, C₁₋₃haloalkoxy,C₁₋₃alkylthio, C₁₋₃haloalkylthio, C₁₋₃ alkylsulfinyl,C₁₋₃haloalkylsulfinyl, C₁₋₃alkylsulfonyl or C₁₋₃haloalkylsulfonyl, withthe proviso that at least one of Y and Z is a bicyclic ring;

W is O, S or an oxetane group;

each R₁ is independently halogen, cyano, hydroxyl, amino,C₁₋₃alkylamino, C₁₋₃ dialkylamino, C₁₋₃alkyl or C₁₋₃haloalkyl;

R₂ and R₃ are independently H, halogen, C₁-C₃alkyl or C₁-C₃haloalkyl;

X₆ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O—, —NH—, —C(O)—NH— and—NH—C(O)—, wherein each —CH₂— in the —(CH₂)_(n)— group, —NH—, —C(O)—NH—and —NH—C(O)— are optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₃hydroxyalkyl, amino, C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃aminoalkyl, C₁₋₃alkyl and C₁₋₃haloalkyl;

X₈ is a bond, —(CH₂)_(n) where n is 1 to 3, —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—, wherein each CH₂in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH— isoptionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃hydroxyalkyl, C₁₋₃aminoalkyl,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃ alkoxyalkyl; n is 0, 1, 2 or 3; and ris 0, 1, 2, 3 or 4;

Q₁, Q₂, Q₃ and Q₄ are each independently C—H or a heteroatom selectedfrom N, S or O;

the dashed lines represent a single or double bond; n is 0, 1, 2 or 3;and r is 0, 1, 2, 3 or 4.

In yet another embodiment of formula (IB-1), W is O, X₆ is —O—, Y and/orZ are independently phenyl, naphthyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl,dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl, each of which isoptionally substituted with one or more halogen, nitro, cyano, alkyl,haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl,with the proviso that at least one of Y or Z is a bicyclic ring; n is 1or 2, R₂ and R₃ are H and r is 0.

In another embodiment of formula (IB-1), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of chloro, fluoro, bromo, CF₃,OCF₃, SCF₃ or SF₅, and the other of Y or Z is phenyl optionallysubstituted by cyano, nitro, CF₃, SF₅, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl,S(O)C₁₋₃haloalkyl or S(O)₂C₁₋₃haloalkyl;

the ring is a trans-cyclohexylene or phenylene ring;

W is O; X₆ is a bond, —O—, —(CH₂)_(n)— where n is 1 to 3 or —NH—;

X₈ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O— or NH—;

R₂ and R₃ are H;

n is 1 or 2; and r is 0.

In another embodiment of formula (IB-1), the ring is optionallysubstituted cyclohexylene or phenylene, W is O, Y and/or Z areindependently optionally substituted naphthyl, benzofuranyl,dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl, X₆ is —O—, n is 1or 2, R₂ and R₃ are H, r is 0; and X₈ is NH—, —C(O)—, —CH₂—, —CF₂—,—CH(CH₃)— or C(CH₃)₂—.

In another embodiment, the invention provides the compounds of formula(IB-1) in Table 4 below.

TABLE 4 Compounds of Formula (IB-1) where W is O, R₂ and R₃ are H, n is1, R¹ is not present, X₆ is —O— and X₈ is —NH—. (IB-1)

Y Ring Z #

trans- C₆H₁₀

192

trans- C₆H₁₀

193

trans- C₆H₁₀

194

trans- C₆H₁₀

195

C₆H₄

196

C₆H₄

197

C₆H₄

198

C₆H₄

199

In one embodiment of formula (IB-2), W is O. In another embodiment, X₁is —O—, —S—, or —NH— in which the hydrogen atom may be replaced withalkyl, haloalkyl or arylalkyl. In yet another embodiment of formula(IB-2), X₆ is —NH— in which the hydrogen may be replaced by alkyl,haloalkyl or arylalkyl; —O—, —S—, —S(O)— or —S(O)₂—. In anotherembodiment, X₆ is —(CH₂)_(n)— optionally substituted by halogen, alkylor haloalkyl. In another embodiment, the ring is an optionallysubstituted cyclohexylene group. In yet another embodiment, the ring isan optionally substituted phenylene group. In still another embodimentof formula (IB-2), R₂ and R₃ are H. In still another embodiment offormula (IB-2), n is 1 or 2.

In yet another embodiment of formula (IB-2), W is O, Y and/or Z areindependently phenyl, naphthyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl,dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl, each of which isoptionally substituted with one or more halogen, nitro, cyano, alkyl,haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl,with the proviso that at least one of Y or Z is a bicyclic ring; X₆ is—O—, X₁ and X₈ are —NH—, n is 1 or 2, R₂ and R₃ are H and r is 0.

In another embodiment of formula (IB-2), Y and Z is phenyl, naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano,C₁₋₃alkyl, C₁₋₃haloalkyl, phenyl, hydroxy, C₁₋₃hydroxyalkyl, amino,C₁₋₃alkyl- or C₁₋₃dialkylamino, C₁₋₃alkoxy, C₁₋₃haloalkoxy,C₁₋₃alkylthio, C₁₋₃haloalkylthio, C₁₋₃alkylsulfinyl,C₁₋₃haloalkylsulfinyl, C₁₋₃ alkylsulfonyl, C₁₋₃haloalkylsulfonyl or SF₅,with the proviso that at least one of Y and Z is a bicyclic ring;

Q₁, Q₂, Q₃ and Q₄ are CH or one or two of Q₁, Q₂, Q₃ and Q₄ areindependently N, O or S and the remaining of Q₁, Q₂, Q₃ and Q₄ are CH;

the dashed lines represent a single or double bond;

X₁ is a bond, —C(O)—, —(CH₂)_(n)— where n is 1 to 3, —O—CH₂—, —NHCH₂—,—S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, and —CH₂—S(O)₂—, whereineach —(CH₂)_(n)—, —O—CH₂—, —NHCH₂—, —S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—,—S(O)₂—CH₂—, and —CH₂—S(O)₂— are optionally substituted with oxo (═O) orone or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups;

W is O, S or an oxetane group;

each R₁ is independently halogen, cyano, hydroxyl, amino,C₁₋₃alkylamino, C₁₋₃ dialkylamino, C₁₋₃alkyl or C₁₋₃haloalkyl;

R₂ and R₃ are independently H, halogen, C₁-C₃alkyl or C₁-C₃haloalkyl;

X₈ is a bond, —(CH₂)_(n) where n is 1 to 3, —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—, wherein each CH₂in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH— isoptionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃hydroxyalkyl, C₁₋₃aminoalkyl,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃ alkoxyalkyl; n is 0, 1, 2 or 3; and ris 0, 1, 2, 3 or 4.

In another embodiment of formula (IB-2), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of chloro, fluoro, bromo, CF₃,OCF₃, SCF₃ or SF₅, and the other of Y or Z is phenyl optionallysubstituted by cyano, nitro, CF₃, SF₅, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl,S(O)C₁₋₃haloalkyl or S(O)₂C₁₋₃haloalkyl;

the ring is a trans-cyclohexylene or phenylene ring;

W is O;

X₆ is a bond, —O—, —(CH₂)_(n)— where n is 1 to 3 or —NH—;

X₈ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O— or NH—;

R₂ and R₃ are H; n is 1 or 2; and r is 0.

In another embodiment of formula (IB-2), the ring is cyclohexylene orphenylene, W is O, Y and/or Z are independently phenyl, naphthyl,quinolinyl, isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl,benzofuranyl, dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl,each of which is optionally substituted with one or more halogen, nitro,cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- ordialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl orhaloalkylsulfonyl, with the proviso that one of Y or Z is a bicyclicring; X₆ is —O—, X₁ is —NH—, n is 1 or 2, R₂ and R₃ are H, r is 0 and X₈is —NH—, —C(O)—, —CH₂—, —CF₂—, —CH(CH₃)— or C(CH₃)₂—.

In another embodiment, the invention provides the compounds of formula(IB-2) in Table 5 below.

TABLE 5 Compounds of formula (IB-2) where W is O, R₂ and R₃ are H, n is1, R¹ is not present, X₆ is —O— and X₈ is —NH—. (IB-2)

Y X₁ Ring Z #

—NH— trans- C₆H₁₀

200

—NH— trans- C₆H₁₀

201

—NH— trans- C₆H₁₀

202

—NH— trans- C₆H₁₀

203

—NH— C₆H₄

204

—NH— C₆H₄

205

—NH— C₆H₄

206

—NH— C₆H₄

207

—NH— trans- C₆H₁₀

208

—NH— trans- C₆H₁₀

209

—NH— trans- C₆H₁₀

210

—NH— trans- C₆H₁₀

211

—NH— C₆H₄

212

—NH— C₆H₄

213

—NH— C₆H₄

214

—NH— C₆H₄

215

In one embodiment of formula (IB-3), W and W′ are each 0. In yet anotherembodiment of formula (IB-3), X₆ is —NH— in which the hydrogen may bereplaced by alkyl, haloalkyl or arylalkyl, —O—, —S—, —S(O)— or —S(O)₂—.In another embodiment, X₆ is (CH₂)_(n)-optionally substituted byhalogen, alkyl or haloalkyl. In another embodiment of formula (IB-3),the ring is an optionally substituted cyclohexylene group. In yetanother embodiment, the ring is an optionally substituted phenylenegroup. In still another embodiment of formula (IB-3), R₂ and R₃ are H.In still another embodiment of formula (IB-3), n is 1 or 2. In anotherembodiment of formula (IB-3), R and R′ is each independently hydrogen oralkyl.

In another embodiment of formula (IB-3), Y and Z are independentlyphenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more of halogen, nitro, cyano,SF₅, C₁₋₃alkyl, C₁₋₃haloalkyl, phenyl, hydroxy, C₁₋₃hydroxyalkyl, amino,C₁₋₃alkyl- or C₁₋₃ dialkylamino, C₁₋₃alkoxy, C₁₋₃haloalkoxy,C₁₋₃alkylthio, C₁₋₃haloalkylthio, C₁₋₃alkylsulfinyl,C₁₋₃haloalkylsulfinyl, C₁₋₃alkylsulfonyl or C₁₋₃haloalkylsulfonyl, withthe proviso that at least one of Y and Z is a bicyclic ring;

W and W′ are independently O, S or an oxetane group;

R and R′ are independently H, C₁₋₃alkyl or C₁₋₃haloalkyl;

each R₁ is independently halogen, cyano, hydroxyl, amino,C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃alkyl or C₁₋₃haloalkyl;

R₂ and R₃ are independently H, halogen, C₁-C₃alkyl or C₁-C₃haloalkyl;

X₆ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O—, —NH—, —C(O)—NH— and—NH—C(O)—, wherein each —CH₂— in the —(CH₂)_(n)— group, —NH—, —C(O)—NH—and —NH—C(O)— are optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₃hydroxyalkyl, amino, C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃aminoalkyl, C₁₋₃alkyl and C₁₋₃haloalkyl;

Q₁, Q₂, Q₃ and Q₄ are CH or one or two of Q₁, Q₂, Q₃ and Q₄ areindependently N, O or S and the remaining of Q₁, Q₂, Q₃ and Q₄ are CH;

the dashed lines represent a single or double bond;

X₈ is absent or is a bond, —(CH₂) where n is 1 to 3, —O—, —C(O)—, —S—,—S(O)—, —S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—, whereineach CH₂ in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—is optionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃hydroxyalkyl, C₁₋₃aminoalkyl,C₁₋₃alkyl, C₁₋₃ haloalkyl and C₁₋₃alkoxyalkyl; n is 0, 1, 2 or 3; and ris 0, 1, 2, 3 or 4.

In yet another embodiment of formula (IB-3), W and W′ are O, X₆ is —O—or —NH—, n is 1 or 2, R₂ and R₃ are H, Y and/or Z are independentlyphenyl, naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolylor benzothiazolyl, each of which is optionally substituted with one ormore halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl,amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy,alkylthio, halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl or haloalkylsulfonyl, with the proviso that at least oneof Y or Z is a bicyclic ring; and r is 0.

In another embodiment of formula (IB-3), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of chloro, fluoro, bromo, CF₃,OCF₃, SCF₃ or SF₅, and the other of Y or Z is phenyl optionallysubstituted by cyano, nitro, CF₃, SF₅, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl,S(O)C₁₋₃haloalkyl or S(O)₂C₁₋₃haloalkyl;

the ring is a trans-cyclohexylene or phenylene ring;

W and W′ are O;

R and R′ are H or C₁₋₃alkyl;

X₆ is a bond, —O—, —(CH₂)_(n)— where n is 1 to 3 or —NH—;

X₈ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O— or —NH—;

R₂ and R₃ are H; n is 1 or 2; and r is 0.

In another embodiment of formula (IB-3), the ring is optionallysubstituted cyclohexylene or phenylene, W and W′ are O, Y and/or Z areindependently optionally substituted phenyl, naphthyl, benzofuranyl,dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl, wherein at leastone of Y or Z is a bicyclic ring; X₆ is —O—, n is 1 or 2, R₂ and R₃ areH, r is 0 and X₈ is —NH—, —C(O)—, —CH₂—, —CF₂—, —CH(CH₃)— or —C(CH₃)₂—.

In one embodiment of formula (IB-4), W and W′ are each 0. In yet anotherembodiment of formula (IB-4), X₆ is —NH— in which the hydrogen may bereplaced by alkyl, haloalkyl or arylalkyl; —O—, —S—, —S(O)— or —S(O)₂—.In another embodiment, X₆ is —(CH₂)_(n)-optionally substituted byhalogen, alkyl or haloalkyl. In another embodiment of formula (IB-4),the ring is an optionally substituted cyclohexylene group. In yetanother embodiment, the ring is an optionally substituted phenylenegroup. In another embodiment, X₁ is —(CH₂)_(n)-optionally substituted byhalogen, alkyl or haloalkyl.

In still another embodiment of formula (IB-4), R₂ and R₃ are H. In stillanother embodiment of formula (IB-4), n is 1 or 2. In another embodimentof formula (IB-4), R and R′ are independently hydrogen or alkyl. In yetanother embodiment of formula (IB-4), W and W′ are O, Y and/or Z areindependently phenyl, naphthyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl,dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl, each of which isoptionally substituted with one or more halogen, nitro, cyano, alkyl,haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl,with the proviso that one of Y or Z are a bicyclic ring; X₆ is —O— or—NH—, n is 1 or 2, R₂ and R₃ are H and r is 0.

In another embodiment of formula (IB-4), Y and Z are independentlyphenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more of halogen, nitro, cyano,SF₅, C₁₋₃alkyl, C₁₋₃haloalkyl, phenyl, hydroxy, C₁₋₃hydroxyalkyl, amino,C₁₋₃alkyl- or C₁₋₃dialkylamino, C₁₋₃alkoxy, C₁₋₃haloalkoxy,C₁₋₃alkylthio, C₁₋₃haloalkylthio, C₁₋₃ alkylsulfinyl,C₁₋₃haloalkylsulfinyl, C₁₋₃alkylsulfonyl or C₁₋₃haloalkylsulfonyl, withthe proviso that at least one of Y and Z is a bicyclic ring;

W and W′ are independently O, S or an oxetane group;

Q₁, Q₂, Q₃ and Q₄ are CH or one or two of Q₁, Q₂, Q₃ and Q₄ areindependently N, O or S and the remaining of Q₁, Q₂, Q₃ and Q₄ are CH;

the dashed lines represent a single or double bond;

R and R′ are independently H, C₁₋₃alkyl or C₁₋₃haloalkyl;

each R₁ is independently halogen, cyano, hydroxyl, amino,C₁₋₃alkylamino, C₁₋₃ dialkylamino, C₁₋₃alkyl or C₁₋₃haloalkyl;

R₂ and R₃ are independently H, halogen, C₁-C₃alkyl or C₁-C₃haloalkyl;

X₆ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O—, —NH—, —C(O)—NH— and—NH—C(O)—, wherein each —CH₂— in the —(CH₂)_(n)— group, —NH—, —C(O)—NH—and —NH—C(O)— are optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,C₁₋₃hydroxyalkyl, amino, C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃aminoalkyl, C₁₋₃alkyl and C₁₋₃haloalkyl;

X₈ is a bond, —(CH₂)_(n) where n is 1 to 3, —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—, wherein each CH₂in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH— isoptionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃hydroxyalkyl, C₁₋₃aminoalkyl,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃ alkoxyalkyl; n is 0, 1, 2 or 3; and ris 0, 1, 2, 3 or 4.

In another embodiment of formula (IB-4), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of chloro, fluoro, bromo, CF₃,OCF₃, SCF₃ or SF₅, and the other of Y or Z is phenyl optionallysubstituted by cyano, nitro, CF₃, SF₅, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl,S(O)C₁₋₃haloalkyl or S(O)₂C₁₋₃haloalkyl;

the ring is a trans-cyclohexylene or phenylene ring;

W and W′ are O;

R and R′ are H or C₁₋₃alkyl;

X₆ is a bond, —O—, —(CH₂)_(n)— where n is 1 to 3 or —NH—;

X₈ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O— or —NH—;

R₂ and R₃ are H; n is 1 or 2; and r is 0.

In yet another embodiment of formula (IB-4), the ring is optionallysubstituted cyclohexylene or phenylene, W and W′ are O, Y and/or Z areindependently phenyl, naphthyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, benzofuranyl,dihydrobenzofuranyl, benzimidazolyl or benzothiazolyl, each of which isoptionally substituted with one or more halogen, nitro, cyano, alkyl,haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl,with the proviso that at least one of Y or Z is a bicyclic ring; X₁ is—(CH₂)_(n)— where n is 1 or 2 optionally substituted by halogen, alkylor haloalkyl; X₆ is —O—, n is 1 or 2; R₂ and R₃ are H; r is 0 and X₈ is—NH—, —C(O)—, —CH₂—, —CF₂—, —CH(CH₃)— or —C(CH₃)₂—.

In another embodiment, the invention provides the compounds of formula(IB-4) in Table 6 below:

TABLE 6 Compounds of formula (IB-4), wherein W and W’ are O, R₂ and R₃are H, n is 2 and X₈ is —NH—: (IB-4)

Y X₁ R R’ X₆ Ring Z #

bond H H O trans- C₆H₁₀

 75

bond H H O trans- C₆H₁₀

172

bond H H O trans- C₆H₁₀

173

bond H H O trans- C₆H₁₀

174

bond Me H O trans- C₆H₁₀

175

bond H Me O trans- C₆H₁₀

176

bond Me Me O trans- C₆H₁₀

177

CH₂ H H O trans- C₆H₁₀

216

CH₂ H H O trans- C₆H₁₀

217

CH₂ H H O trans- C₆H₁₀

218

CH₂ H H O trans- C₆H₁₀

219

CH₂ H H O trans- C₆H₁₀

220

CH₂ H H O trans- C₆H₁₀

221

CH₂ H H O trans- C₆H₁₀

222

CH₂ H H O trans- C₆H₁₀

223

bond H H O trans- C₆H₁₀

238

bond H H O trans- C₆H₁₀

239

bond H H O trans- C₆H₁₀

240

bond H H O trans- C₆H₁₀

241

bond Me H O trans- C₆H₁₀

242

bond Me Me O trans- C₆H₁₀

244

bond H H O trans- C₆H₁₀

382

bond Me H O trans- C₆H₁₀

383

bond H Me O trans- C₆H₁₀

384

bond Me Me O trans- C₆H₁₀

385

bond H H O trans- C₆H₁₀

386

bond Me H O trans- C₆H₁₀

387

bond H Me O trans- C₆H₁₀

388

bond Me Me O trans- C₆H₁₀

389

CH₂ H H O C₆H₄

224

CH₂ H H O C₆H₄

225

CH₂ H H O C₆H₄

226

CH₂ H H O C₆H₄

227

CH₂ H H O C₆H₄

228

CH₂ H H O C₆H₄

229

CH₂ H H O C₆H₄

230

CH₂ H H O C₆H₄

231

In another aspect of the invention, the compounds of formula (I) havethe structure (IC) shown below:

Wherein variables Y, X₁, and Z are as defined for formula (I), Ring A isindependently a monocyclic 3- to 8-membered carbocyclylene orheterocyclylene ring or a 7- to 11-membered carbocyclylene orheterocyclylene ring, wherein the heterocyclylene ring may contain 1 to4 heteroatoms selected from O, S and N; and the Linker is the segment—X₃—X₄—X₅—X₆—X₇—X₈— where X₃, X₄, X₅, X₆, X₇ and X₈ are as defined forformula (I).

In one embodiment of formula (IC), Y and/or Z is naphthyl which isoptionally substituted with one or more of halogen, nitro, cyano,hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl,alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio,arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl,heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio,heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio,heteroarylalkylsulfinyl or heteroarylalkylsulfonyl.

In another embodiment of formula (IC), Y and/or Z are independentlybenzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl each of which isoptionally substituted with one or more of halogen, nitro, cyano,hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl,alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio,arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl,heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio,heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio,heteroarylalkylsulfinyl or heteroarylalkylsulfonyl.

In another embodiment of formula (IC), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl andthe other of Y or Z is phenyl, a 3-7 membered heterocyclyl group or a 5or 6-membered heteroaryl group, each of which is optionally substitutedby one or more of halogen, nitro, cyano, alkyl, haloalkyl, phenyl,hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl,alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In still another embodiment of formula (IC), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl andthe other of Y or Z is phenyl or a 5- or 6-membered heteroaryl group,each of which is optionally substituted by one or more of halogen,nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino,alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio,halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonylor haloalkylsulfonyl.

In another embodiment, one of Y or Z is naphthyl, benzofuranyl,dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl,benzimidazolyl, or benzothiazolyl, each of which is optionallysubstituted by one or more of chloro, fluoro, bromo, CF₃, OCF₃, SCF₃halothio, and the other of Y or Z is phenyl optionally substituted bycyano, nitro, CF₃, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl, S(O)C₁₋₃haloalkyl orS(O)₂C₁₋₃haloalkyl.

In one embodiment of formula (IC), Ring A is a 5- or -6-memberedheterocycle containing one or more nitrogen atoms. In anotherembodiment, Ring A is an optionally substituted cyclohexylene ring. Instill another embodiment, Ring A is an optionally substituted phenylenering. In yet another embodiment, Ring A is L1 to L10 or L13 to L18 inTable 1 above. In another embodiment, Ring A is L1, L2, L3, L4, L5, L6,L7, L8, L13, L14, L15, L16, L17 or L18. In still another embodiment,Ring A is L1, L4, L13, L14 or L15.

In one embodiment of formula (IC), the compound has the structure (IC-1)shown below:

wherein Y, X₈ and Z are as defined for formula (I) above; Ring A is a 3to 8-membered monocyclic carbocyclic or heterocylic ring wherein Q₅ andQ₆ are independently N or CR₄ where R₄ is H, halogen, OH or C₁₋₃alkyl;X₁ is a bond, —C(O)—, —C(S)—, —NH—, —S(O)—, —S(O)₂—, —(CH₂)_(n)— where nis 1 to 3, —O—CH₂—, —NHCH₂—, —S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—,—S(O)₂—CH₂—, or —CH₂—S(O)₂—, wherein each —NH—, —(CH₂)_(n)—, —O—CH₂—,—NHCH₂—, —S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, and —CH₂—S(O)₂—are optionally substituted with oxo (═O) or one or more halogen, cyano,alkyl, haloalkyl, cycloalkyl or aryl groups; W is O, S or oxetane; R₂and R₃ are independently hydrogen, halogen, cyano, alkyl, haloalkyl orcarbocyclyl; and n is 1, 2 or 3.

In one embodiment of formula (IC-1), W is O. In another embodiment, RingA is one of linkers L1, L2, L3, L4, L5, L6, L7, L8, L9, L10, L13, L14,L15, L16, L17 or L18. In another embodiment, Ring A is one of L1, L2,L3, L4, L5, L6, L7, L8, L13, L14, L15, L16, L17 or L18. In yet anotherembodiment, Ring A is L1, L4, L5, L13, L14 or L15. In anotherembodiment, Ring A is L1 or L4.

In still another embodiment of formula (IC-1), Y and/or Z is naphthylwhich is optionally substituted with one or more halogen, nitro, cyano,alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In yet another embodiment of formula (IC-1), Y and/or Z areindependently benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted with one or more halogen, nitro, cyano,alkyl, haloalkyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In another embodiment of formulae (IC-1), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl and the other of Yor Z is phenyl, a 3-8 membered heterocyclyl group or a 5 or 6-memberedheteroaryl group, each of which is optionally substituted by one or moreof halogen, nitro, cyano, alkyl, haloalkyl, phenyl, hydroxy,hydroxyalkyl, amino, alkyl- or dialkylamino, aminoalkyl, alkoxy,haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl or haloalkylsulfonyl.

In still another embodiment of formula (IC-1), one of Y or Z isnaphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of halogen, nitro, cyano, alkyl,haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- or dialkylamino,aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio, alkylsulfinyl,haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl, and the other ofY or Z is phenyl or a 5- or 6-membered heteroaryl group, each of whichis optionally substituted by one or more of halogen, nitro, cyano,alkyl, haloalkyl, phenyl, hydroxy, hydroxyalkyl, amino, alkyl- ordialkylamino, aminoalkyl, alkoxy, haloalkoxy, alkylthio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl or haloalkylsulfonyl.

In another embodiment, one of Y or Z is naphthyl, benzofuranyl,dihydrobenzofuranyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, indolyl, isoindolyl, benzothiophenyl,benzimidazolyl, or benzothiazolyl, each of which is optionallysubstituted by one or more of chloro, fluoro, bromo, CF₃, OCF₃ or SCF₃,and the other of Y or Z is phenyl optionally substituted by cyano,nitro, CF₃, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl, S(O)C₁₋₃haloalkyl orS(O)₂C₁₋₃haloalkyl.

In another embodiment, X₁ is optionally substituted —(CH₂)_(n)— or—C(O)—. In another embodiment, X₈ is —C(O)— or optionally substituted—NH— or —(CH₂)_(n)—. In still another embodiment of formula (IC-1), R₂and R₃ are H. In still another embodiment of formula (IC-1), n is 1 or2. In yet another embodiment of formula (IC-1), X₁ is a bond, —C(O)— or—CH₂—; W is O, n is 1 or 2, and R₂ and R₃ are H.

In another embodiment of formula (IC-1), Y and Z are independentlyphenyl, naphthyl, benzofuranyl, dihydrobenzofuranyl, quinolinyl,isoquinolinyl, tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl,isoindolyl, benzothiophenyl, benzimidazolyl, or benzothiazolyl, each ofwhich is optionally substituted by one or more of halogen, nitro, cyano,C₁₋₃alkyl, C₁₋₃haloalkyl, phenyl, hydroxy, C₁₋₃hydroxyalkyl, amino,C₁₋₃alkyl- or C₁₋₃ dialkylamino, C₁₋₃alkoxy, C₁₋₃haloalkoxy,C₁₋₃alkylthio, C₁₋₃haloalkylthio, C₁₋₃ alkylsulfinyl,C₁₋₃haloalkylsulfinyl, C₁₋₃alkylsulfonyl or C₁₋₃haloalkylsulfonyl, withthe proviso that at least one of Y and Z is a bicyclic ring;

X₁ is a bond, —C(O)—, —(CH₂)_(n)— where n is 1 to 3, —O—CH₂—, —NHCH₂—,—S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, and —CH₂—S(O)₂—, whereineach —(CH₂)_(n)—, —O—CH₂—, —NHCH₂—, —S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—,—S(O)₂—CH₂—, and —CH₂—S(O)₂— are optionally substituted with oxo (═O) orone or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups;

Ring A is a 3-8 membered heterocyclic ring wherein Q₅ and Q₆ areindependently N or CR₄ where R₄ is H, OH, halogen or C₁-C₃alkyl;

W is O, S or an oxetane group;

R₂ and R₃ are independently H, halogen, C₁-C₃alkyl or C₁-C₃haloalkyl;

X₈ is a bond, —(CH₂)_(n) where n is 1 to 3, —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH—, wherein each CH₂in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or —NH— isoptionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,C₁₋₃alkylamino, C₁₋₃dialkylamino, C₁₋₃hydroxyalkyl, C₁₋₃aminoalkyl,C₁₋₃alkyl, C₁₋₃haloalkyl and C₁₋₃ alkoxyalkyl; and n is 0, 1, 2 or 3.

In another embodiment of formula (IC-1), one of Y or Z is naphthyl,benzofuranyl, dihydrobenzofuranyl, quinolinyl, isoquinolinyl,tetrahydroquinolyl, tetrahydroisoquinolyl, indolyl, isoindolyl,benzothiophenyl, benzimidazolyl, or benzothiazolyl, each of which isoptionally substituted by one or more of chloro, fluoro, bromo, CF₃,OCF₃ or SCF₃, and the other of Y or Z is phenyl optionally substitutedby cyano, nitro, CF₃, S(O)C₁₋₃alkyl, S(O)₂—C₁₋₃alkyl, S(O)C₁₋₃haloalkylor S(O)₂C₁₋₃haloalkyl;

Ring A is L1, L2, L3, L8, L13, L14, L15 or L16;

W is O; X₆ is a bond, —O—, —(CH₂)_(n)— where n is 1 to 3 or —NH—;

X₈ is a bond, —(CH₂)_(n)— where n is 1 to 3, —O— or —NH—;

R₂ and R₃ are H; and

n is 1 or 2. In another embodiment of formula (IC-1), Ring A isoptionally substituted cyclohexylene or phenylene, Y and/or Z areindependently naphthyl, quinolinyl, isoquinolinyl, tetrahydroquinolyl,tetrahydroisoquinolyl, benzofuranyl, dihydrobenzofuranyl, benzimidazolylor benzothiazolyl, each of which is optionally substituted with one ormore halogen, nitro, cyano, alkyl, haloalkyl, hydroxy, hydroxyalkyl,amino, alkyl- or dialkylamino, aminoalkyl, alkoxy, haloalkoxy,alkylthio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl or haloalkylsulfonyl; X₁ is bond, —C(O)— or —CH₂—; W is O,n is 1 or 2, R₂ and R₃ are H, and X₈ is —NH—, —C(O)—, —CH₂—, —CF₂—,—CH(CH₃)— or —C(CH₃)₂—.

In another embodiment, the invention provides the compounds of formula(IC) in table 7 below:

TABLE 7 Compounds of formula (IC-1), wherein X1 is a bond, W is O, R₂and R₃ are H, n is 1 and X₈ is —O—. (IC-1)

Ring Y A Z #

L1

111

L1

112

L1

113

L1

114

L1

127

L1

128

L1

129

L1

130

L1

131

The compounds of the invention were found to exhibit superiorpermeability compared with prior art compounds. For an orally-dosedcompound the permeability of a compound across the epithelium cellsalong the gastrointestinal tract is an important limiting factor for theoral absorption and systemic availability of the compound. Thus, thepermeability of a systemically-acting compound is a feature that cansignificantly impact the efficacy of a compound against internal and/orexternal parasites when administered orally or topically.

In one embodiment, the compounds of the invention exhibit surprisinglyimproved permeability compared with the compounds of the prior arthaving only monocyclic rings at the position corresponding to Y and/or Z(for example compounds of WO 2009/077527 and EP 2468096). Thesignificantly higher permeability of the compounds of the invention isexpected to result in higher in vivo efficacy against internal parasitessuch as nematodes and external parasites that consume blood meals. Thisis because the increased permeability across the mammalian gut enhancesthe amount of the active compounds present in the blood circulation fordelivery and uptake at the required sites. Furthermore, the increasedpermeability of the compounds is likely to result in increasedpermeability across the nematode tissue. In addition, increasedpermeability of the active compounds may result in improved transdermalpassage of the compounds into the bloodstream following topicaladministration.

In one embodiment, the compounds of the invention exhibit about 20% toabout 30% higher permeability than the prior art compounds. In anotherembodiment, the compounds of the invention exhibit about 40% to about60% or about 50% to about 70% higher permeability than the prior artcompounds. In still other embodiments, the compounds of the inventionexhibit about 60% to about 100% higher permeability. In yet otherembodiments, the compounds of the invention exhibit about 20% to about50% or about 30% to about 75% higher permeability compared with theprior art compounds. In yet other embodiments, the compounds of theinvention exhibit about 50% to about 100% higher permeability comparedwith the prior art compounds.

In other embodiments, the compounds of the invention exhibit about 50%to about 500% greater permeability than the prior art compounds. Inother embodiments, the compounds of the invention exhibit about 100% toabout 500% greater permeability than the prior art compounds. In yetother embodiments, the compounds of the invention exhibit about 200% toabout 400% greater permeability. In other embodiments, the compounds ofthe invention exhibit In yet other embodiments, the compounds of theinvention exhibit about 100% to about 300% higher permeability or about200% to about 300% greater permeability than the prior art compounds. Inyet other embodiments, the compounds of the invention exhibit about 100%to about 200% higher permeability compared with the prior art compounds.In other embodiments, the compounds of the invention exhibit about 300%to about 500% higher permeability or about 400% to about 500% higherpermeability compared with the prior art compounds.

COMPOSITIONS OF THE INVENTION

In another aspect, the invention provides parasiticidal compositionswhich comprise at least one anthelmintic compound of formula (I) of theinvention and a pharmaceutically acceptable carrier. The composition ofthe invention can also be in a variety of forms which include, but arenot limited to, oral formulations, injectable formulations, and topical,dermal or subdermal formulations. The formulations are intended to beadministered to an animal which includes but is not limited to mammals,birds and fish. Examples of mammals include but are not limited tohumans, cattle, sheep, goats, llamas, alpacas, pigs, horses, donkeys,dogs, cats and other livestock or domestic mammals. Examples of birdsinclude turkeys, chickens, ostriches and other livestock or domesticbirds.

The composition of the invention may be in a form suitable for oral use,for example, as baits (see, e.g., U.S. Pat. No. 4,564,631, incorporatedherein by reference), dietary supplements, troches, lozenges, chewables,tablets, hard or soft capsules, emulsions, aqueous or oily suspensions,aqueous or oily solutions, oral drench formulations, dispersible powdersor granules, premixes, syrups or elixirs, enteric formulations orpastes. Compositions intended for oral use may be prepared according toany method known in the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, butteringagents, flavoring agents, coloring agents and preserving agents in orderto provide pharmaceutically elegant and palatable preparations.

Tablets may contain the active ingredient in admixture with non-toxic,pharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example,magnesium stearate, stearic acid or talc, the tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate may be employed. They mayalso be coated by the technique described in U.S. Pat. Nos. 4,256,108;4,166,452; and 4,265,874 (incorporated herein by reference) to formosmotic therapeutic tablets for controlled release.

Formulations for oral use may be hard gelatin capsules, wherein theactive ingredient is mixed with an inert solid diluent, for example,calcium carbonate, calcium phosphate or kaolin. Capsules may also besoft gelatin capsules, wherein the active ingredient is mixed with wateror miscible solvents such as propylene glycol, PEGs and ethanol, or anoil medium, for example peanut oil, liquid paraffin, or olive oil.

The compositions of the invention may also be in the form ofoil-in-water or water-in-oil emulsions. The oily phase may be avegetable oil, for example, olive oil or arachis oil, or a mineral oil,for example, liquid paraffin or mixtures of these. Suitable emulsifyingagents may be naturally-occurring phosphatides, for example, soybean,lecithin, and esters or partial esters derived from fatty acids andhexitol anhydrides, for example, sorbitan monoleate, and condensationproducts of the said partial esters with ethylene oxide, for example,polyoxyethylene sorbitan monooleate. The emulsions may also containsweetening agents, bittering agents, flavoring agents, and/orpreservatives.

In one embodiment of the formulation, the composition of the inventionis in the form of a microemulsion. Microemulsions are well suited as theliquid carrier vehicle. Microemulsions are quaternary systems comprisingan aqueous phase, an oily phase, a surfactant and a co-surfactant. Theyare translucent and isotropic liquids.

Microemulsions are composed of stable dispersions of microdroplets ofthe aqueous phase in the oily phase or conversely of microdroplets ofthe oily phase in the aqueous phase. The size of these microdroplets isless than 200 nm (1000 to 100,000 nm for emulsions). The interfacialfilm is composed of an alternation of surface-active (SA) andco-surface-active (Co-SA) molecules which, by lowering the interfacialtension, allows the microemulsion to be formed spontaneously.

In one embodiment of the oily phase, the oily phase can be formed frommineral or vegetable oils, from unsaturated polyglycosylated glyceridesor from triglycerides, or alternatively from mixtures of such compounds.In one embodiment of the oily phase, the oily phase comprises oftriglycerides; in another embodiment of the oily phase, thetriglycerides are medium-chain triglycerides, for example C₈-C₁₀caprylic/capric triglyceride. In another embodiment of the oily phasewill represent a % v/v range selected from the group consisting of about2 to about 15%; about 7 to about 10%; and about 8 to about 9% v/v of themicroemulsion.

The aqueous phase includes, for example water or glycol derivatives,such as propylene glycol, glycol ethers, polyethylene glycols orglycerol. In one embodiment of the glycol derivatives, the glycol isselected from the group consisting of propylene glycol, diethyleneglycol monoethyl ether, dipropylene glycol monoethyl ether and mixturesthereof. Generally, the aqueous phase will represent a proportion fromabout 1 to about 4% v/v in the microemulsion.

Surfactants for the microemulsion include diethylene glycol monoethylether, dipropyelene glycol monomethyl ether, polyglycolized C₈-C₁₀glycerides or polyglyceryl-6 dioleate. In addition to these surfactants,the co-surfactants include short-chain alcohols, such as ethanol andpropanol.

Some compounds are common to the three components discussed above, i.e.,aqueous phase, surfactant and co-surfactant. However, it is well withinthe skill level of the practitioner to use different compounds for eachcomponent of the same formulation. In one embodiment for the amount ofsurfactant/co-surfactant, the co-surfactant to surfactant ratio will befrom about 1/7 to about ½. In another embodiment for the amount ofco-surfactant, there will be from about 25 to about 75% v/v ofsurfactant and from about 10 to about 55% v/v of co-surfactant in themicroemulsion.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as sucrose, saccharinor aspartame, bittering agents, and flavoring agents may be added toprovide a palatable oral preparation. These compositions may bepreserved by the addition of an anti-oxidant such as ascorbic acid, orother known preservatives.

Aqueous suspensions may contain the active material in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example, sodiumcarboxymethylcellulose, methylcellulose, hydroxy-propylmethylcellulose,sodium alginate, polvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example lecithin, or condensation products of an alkylene oxide withfatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample, heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide, with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl, p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agentsand/or bittering agents, such as those set forth above.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example, sweetening, bittering, flavoring andcoloring agents, may also be present.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, propylene glycol, sorbitol or sucrose. Suchformulations may also contain a demulcent, a preservative, flavoringagent(s) and/or coloring agent(s).

In another embodiment of the invention, the composition can be in pasteform. Examples of embodiments in a paste form include but are notlimited to those described in U.S. Pat. Nos. 6,787,342 and 7,001,889(each of which are incorporated herein by reference). In addition to theanthelmintic compounds of the invention, the paste can also containfumed silica; a viscosity modifier; a carrier; optionally, an absorbent;and optionally, a colorant, stabilizer, surfactant, or preservative.

The process for preparing a paste formulation comprises the steps of:

(a) dissolving or dispersing the anthelmintic compound into the carrierby mixing;(b) adding the fumed silica to the carrier containing the dissolvedanthelmintic compound and mixing until the silica is dispersed in thecarrier;(c) allowing the intermediate formed in (b) to settle for a timesufficient in order to allow the air entrapped during step (b) toescape; and(d) adding the viscosity modifier to the intermediate with mixing toproduce a uniform paste.

The above steps are illustrative, but not limiting. For example, step(a) can be the last step.

In one embodiment of the formulation, the formulation is a pastecontaining at least one anthelmintic compound of formula (I), fumedsilica, a viscosity modifier, an absorbent, a colorant; and ahydrophilic carrier which is triacetin, a monoglyceride, a diglyceride,or a triglyceride.

The paste may also include, but is not limited to, a viscosity modifierselected from the group consisting of PEG 200, PEG 300, PEG 400, PEG600, monoethanolamine, triethanolamine, glycerol, propylene glycol,polyoxyethylene (20) sorbitan mono-oleate (POLYSORBATE 80 or TWEEN 80),and poloxomers (e.g., PLURONIC L 81); an absorbent selected from thegroup consisting of magnesium carbonate, calcium carbonate, starch, andcellulose and its derivatives; and a colorant selected from the groupconsisting of titanium dioxide iron oxide, and FD&C Blue #1 ALUMINUMLAKE.

The compositions may be in the form of a sterile injectable aqueous oroleagenous suspension. This suspension may be formulated according tothe known art using those suitable dispersing or wetting agents andsuspending agents which have been mentioned above. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally-acceptable diluent or solvent,for example, as a solution in 1,3-butane diol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solutionand isotonic sodium chloride solution. Co-solvents such as ethanol,propylene glycol glycerol formal or polyethylene glycols may also beused. Preservatives, such as phenol or benzyl alcohol, may be used.

In addition, sterile, fixed oils are conventionally employed as asolvent or suspending medium. For this purpose any bland fixed oil maybe employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation of injectablecompositions.

Topical, dermal and subdermal formulations can include emulsions,creams, ointments, gels, pastes, powders, shampoos, pour-onformulations, ready-to-use formulations, spot-on solutions andsuspensions, dips and sprays. Topical application of an inventivecompound or of a composition including at least one inventive compoundamong active agent(s) therein, a spot-on or pour-on composition, canallow for the inventive compound to be absorbed through the skin toachieve systemic levels, distributed through the sebaceous glands or onthe surface of the skin achieving levels throughout the hair coat. Whenthe compound is distributed through the sebaceous glands, they can actas a reservoir, whereby there can be a long-lasting effect (up toseveral months) effect. Spot-on formulations are typically applied in alocalized region which refers to an area other than the entire animal.In one embodiment of a localized region, the location is between theshoulders. In another embodiment of a localized region it is a stripe,e.g. a stripe from head to tail of the animal.

Pour-on formulations are described in U.S. Pat. No. 6,010,710,incorporated herein by reference. The pour-on formulations may beadvantageously oily, and generally comprise a diluent or vehicle andalso a solvent (e.g. an organic solvent) for the active ingredient ifthe latter is not soluble in the diluent.

Organic solvents that can be used in the invention include but are notlimited to: acetyltributyl citrate, fatty acid esters such as thedimethyl ester, acetone, acetonitrile, benzyl alcohol, butyl diglycol,dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether,ethanol, isopropanol, methanol, ethylene glycol monoethyl ether,ethylene glycol monomethyl ether, monomethylacetamide, dipropyleneglycol monomethyl ether, liquid polyoxyethylene glycols, propyleneglycol, 2-pyrrolidone including N-methylpyrrolidone, diethylene glycolmonoethyl ether, propylene glycol monomethyl ether, propylene glycolmonoethyl ether, ethylene glycol, diisobutyl adipate, diisopropyladipate (also known as CERAPHYL 230), triacetin, butyl acetate, octylacetate, propylene carbonate, butylene carbonate, dimethylsulfoxide,organic amides including dimethylformamide and dimethylacetamide, anddiethyl phthalate, or a mixture of at least two of these solvents.

In one embodiment of the invention, the pharmaceutically or veterinarilyacceptable carrier of the formulation comprises C₁-C₁₀ alcohols oresters thereof (including acetates, such as ethyl acetate, butyl acetateand the like), C₁₀-C₁₈ saturated fatty acids or esters thereof, C₁₀-C₁₈monounsaturated fatty acids or esters thereof, monoesters or diesters ofaliphatic diacids, glycerol monoesters (e.g. monoglycerides), glyceroldiesters (e.g. diglycerides), glycerol triesters (e.g. triglyceridessuch as triacetin), glycols, glycol ethers, glycol esters or glycolcarbonates, polyethylene glycols of various grades (PEGs) or monoethers,diethers, monoesters or diesters thereof (e.g. diethylene glycolmonoethyl ether), or mixtures thereof.

As vehicle or diluent, mention may be made of plant oils such as, butnot limited to soybean oil, groundnut oil, castor oil, corn oil, cottonoil, olive oil, grape seed oil, sunflower oil, coconut oils etc.;mineral oils such as, but not limited to, petrolatum, paraffin,silicone, etc.; aliphatic or cyclic hydrocarbons or alternatively, forexample, medium-chain (such as C8 to C12) triglycerides.

In another embodiment of the invention, an emollient and/or spreadingand/or film-forming agent can be added. One embodiment of the emollientand/or spreading and/or film-forming agent are those agents selectedfrom the group consisting of:(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and vinylpyrrolidone, polyethylene glycols, benzyl alcohol,2-pyrrolidones including, but not limited to N-methylpyrrolidone,mannitol, glycerol, sorbitol, polyoxyethylenated sorbitan esters;lecithin, sodium carboxymethylcellulose, silicone oils,polydiorganosiloxane oils (such as polydimethylsiloxane (PDMS) oils),for example those containing silanol functionalities, or a 45V2 oil,(b) anionic surfactants such as alkaline stearates, sodium, potassium orammonium stearates; calcium stearate, triethanolamine stearate; sodiumabietate; alkyl sulfates (e.g. sodium lauryl sulfate and sodium cetylsulfate); sodium dodecylbenzenesulfonate, sodium dioctylsulfosuccinate;fatty acids (e.g. those derived from coconut oil),(c) cationic surfactants such as water-soluble quaternary ammonium saltsof formula N⁺R′R″R′″R″″, Y⁻ in which the radicals R are optionallyhydroxylated hydrocarbon radicals and Y⁻ is an anion of a strong acidsuch as the halide, sulfate and sulfonate anions; cetyltrimethylammoniumbromide is among the cationic surfactants which can be used,(d) amine salts of formula N⁺HR′R″R′″ in which the radicals R, R′, R″and R′″ are optionally independently hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is among the cationic surfactants which canbe used,(e) nonionic surfactants such as sorbitan esters, which are optionallypolyoxyethylenated (e.g. POLYSORBATE 80), polyoxyethylenated alkylethers; polyoxypropylated fatty alcohols such as polyoxypropylene-styrolether; polyethylene glycol stearate, polyoxyethylenated derivatives ofcastor oil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids, copolymers of ethylene oxide andpropylene oxide,(f) amphoteric surfactants such as the substituted lauryl compounds ofbetaine; or(g) a mixture of at least two of these agents.

The solvent will be used in proportion with the concentration of theanthelmintic compound of formula (I) and its solubility in this solvent.It will be sought to have the lowest possible volume. The vehicle makesup the difference to 100%.

In one embodiment of the amount of emollient, the emollient is used in aproportion of from 0.1 to 50% and 0.25 to 5%, by volume.

In another embodiment of the invention, the composition can be inready-to-use solution form as is described in U.S. Pat. No. 6,395,765,incorporated herein by reference. In addition to the anthelminticcompound of the invention, the ready-to-use solution can contain acrystallization inhibitor, an organic solvent and an organic co-solvent.

In one embodiment of the amount of crystallization inhibitor, thecrystallization inhibitor can be present in a proportion of about 1 toabout 30% (w/v) in the composition. In other embodiments, thecrystallization inhibitor may be present in a proportion of about 1 toabout 20% (w/v) and about 5 to about 15%. Acceptable inhibitors arethose whose addition to the formulation inhibits the formation ofcrystals when the formulation is applied. In some embodiments,formulations may include compounds that function as crystallizationinhibitors other than those listed herein. In these embodiments, thesuitability of a crystallization inhibitor may be determined by a thetest in which 0.3 ml of a solution comprising 10% (w/v) of ananthelmintic compound of the invention in the liquid carrier and 10% ofthe inhibitor are deposited on a glass slide at 20° C. and allowed tostand for 24 hours. The slide is then observed with the naked eye.Acceptable inhibitors are those whose addition provides for few (e.g.less than ten crystals) or no crystal.

In one embodiment, the organic solvent has a dielectric constant of arange selected from the group consisting of between about 2 to about 35,about 10 to about 35 or about 20 to about 30. In other embodiments, thesolvent will have a dielectric constant of between about 2 and about 20,or between about 2 and about 10. The content of this organic solvent inthe overall composition represents the complement to 100% of thecomposition.

As discussed above, the solvent may comprise a mixture of solventsincluding a mixture of an organic solvent and an organic co-solvent. Inone embodiment, and the organic co-solvent has a boiling point of lessthan about 300° C. or less than about 250° C. In other embodiments, theco-solvent has a boiling point of below about 200° C., or below about130° C. In still another embodiment of the invention, the organicco-solvent has a boiling point of below about 100° C., or below about80° C. In still other embodiments, the organic co-solvent will have adielectric constant of a range selected from the group consisting ofabout 2 to about 40, about 10 to about 40, or typically about 20 toabout 30. In some embodiments of the invention, this co-solvent may bepresent in the composition in an organic co-solvent/organic solventweight/weight (W/W) ratio of about 1/15 to about ½. In some embodiments,the co-solvent is volatile so as to act as a drying promoter, and ismiscible with water and/or with the organic solvent.

The formulation can also comprise an antioxidizing agent intended toinhibit oxidation in air, this agent being present in a proportionselected from a range consisting of about 0.005 to about 1% (w/v) andabout 0.01 to about 0.05%.

Crystallization inhibitors which are useful for the invention includebut are not limited to:

(a) polyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinylacetate and of vinylpyrrolidone, polyethylene glycols of various grades,benzyl alcohol, 2-pyrrolidones including, but not limited toN-methylpyrrolidone, dimethylsulfoxide, mannitol, glycerol, sorbitol orpolyoxyethylenated esters of sorbitan; lecithin or sodiumcarboxymethylcellulose; a solvent as described herein that is capable ofinhibiting crystal formation; acrylic derivatives, such as acrylates andmethacrylates or other polymers derived from acrylic monomers, andothers;(b) anionic surfactants, such as alkaline stearates (e.g. sodium,potassium or ammonium stearate); calcium stearate or triethanolaminestearate; sodium abietate; alkyl sulfates, which include but are notlimited to sodium lauryl sulfate and sodium cetyl sulfate; sodiumdodecylbenzenesulfonate or sodium dioctyl sulfosuccinate; or fatty acids(e.g. coconut oil);(c) cationic surfactants, such as water-soluble quaternary ammoniumsalts of formula N⁺R′R″R′″R″″Y⁻, in which the R radicals are identicalor different optionally hydroxylated hydrocarbon radicals and Y is ananion of a strong acid, such as halide, sulfate and sulfonate anions;cetyltrimethylammonium bromide is one of the cationic surfactants whichcan be used;(d) amine salts of formula N⁺HR′R″R′″, in which the R radicals areidentical or different optionally hydroxylated hydrocarbon radicals;octadecylamine hydrochloride is one of the cationic surfactants whichcan be used;(e) non-ionic surfactants, such as optionally polyoxyethylenated estersof sorbitan, e.g. POLYSORBATE 80, or polyoxyethylenated alkyl ethers;polyethylene glycol stearate, polyoxyethylenated derivatives of castoroil, polyglycerol esters, polyoxyethylenated fatty alcohols,polyoxyethylenated fatty acids or copolymers of ethylene oxide and ofpropylene oxide;(f) amphoteric surfactants, such as substituted lauryl compounds ofbetaine; or(g) a mixture of at least two of the compounds listed in (a)-(f) above.In one embodiment of the crystallization inhibitor, a crystallizationinhibitor pair will be used. Such pairs include, for example, thecombination of a film-forming agent of polymeric type and of asurface-active agent. These agents will be selected from the compoundsmentioned above as crystallization inhibitor.

In one embodiment of the film-forming agent, the agents are of thepolymeric type which include but are not limited to the various gradesof polyvinylpyrrolidone, polyvinyl alcohols, and copolymers of vinylacetate and of vinylpyrrolidone.

In one embodiment of the surface-active agents, the agents include butare not limited to those made of non-ionic surfactants; in anotherembodiment of the surface active agents, the agent is apolyoxyethylenated esters of sorbitan and in yet another embodiment ofthe surface-active agent, the agents include the various grades ofPOLYSORBATE, for example POLYSORBATE 80.

In another embodiment of the invention, the film-forming agent and thesurface-active agent can be incorporated in similar or identical amountswithin the limit of the total amounts of crystallization inhibitormentioned elsewhere.

The pair thus constituted secures, in a noteworthy way, the objectivesof absence of crystallization on the coat and of maintenance of thecosmetic appearance of the skin or fur, that is to say without atendency towards sticking or towards a sticky appearance, despite thehigh concentration of active material.

In one embodiment of the antioxidizing agents, the agents are thoseconventional in the art and include but is not limited to butylatedhydroxyanisole, butylated hydroxytoluene, ascorbic acid, sodiummetabisulphite, propyl gallate, sodium thiosulfate or a mixture of notmore than two of them.

The formulation adjuvants discussed above are well known to thepractitioner in this art and may be obtained commercially or throughknown techniques. These concentrated compositions are generally preparedby simple mixing of the constituents as defined above; advantageously,the starting point is to mix the active material in the main solvent andthen the other ingredients or adjuvants are added.

The volume applied is not restricted as long as the amount of substanceadministered is shown to be safe and efficacious. Typically, the volumeapplied depends on the size and weight of the animal as well as theconcentration of active, the extent of infestation by parasites and thetype of administration. In some embodiments, the volume applied can beof the order of about 0.3 to about 5 ml or about 0.3 ml to about 1 ml.In one embodiment for the volume, the volume is on the order of about0.5 ml, for cats and on the order of about 0.3 to about 3 ml for dogs,depending on the weight of the animal.

In another embodiment of the invention, application of a spot-onformulation according to the present invention can also providelong-lasting and broad-spectrum efficacy when the solution is applied tothe mammal or bird. The spot-on formulations provide for topicaladministration of a concentrated solution, suspension, microemulsion oremulsion for intermittent application to a spot on the animal, generallybetween the two shoulders (solution of spot-on type).

For spot-on formulations, the carrier can be a liquid carrier vehicle asdescribed in U.S. Pat. No. 6,426,333 (incorporated herein by reference),which in one embodiment of the spot-on formulation comprises a solventand a co-solvent wherein the solvent is selected from the groupconsisting of acetone, acetonitrile, benzyl alcohol, butyl diglycol,dimethylacetamide, dimethylformamide, dipropylene glycol n-butyl ether,propylene glycol monomethyl ether, propylene glycol monoethyl ether,diisobutyl adipate, diisopropyl adipate (also known as CERAPHYL 230),triacetin, butyl acetate, octyl acetate, propylene carbonate, butylenecarbonate, dimethylsulfoxide, organic amides including dimethylformamideand dimethylacetamide, ethanol, isopropanol, methanol, ethylene glycolmonoethyl ether, ethylene glycol monomethyl ether, monomethylacetamide,dipropylene glycol monomethyl ether, liquid polyoxyethylene glycols,propylene glycol, 2-pyrrolidone including N-methylpyrrolidone,diethylene glycol monoethyl ether, ethylene glycol, diethyl phthalatefatty acid esters, such as the diethyl ester or diisobutyl adipate, anda mixture of at least two of these solvents and the co-solvent isselected from the group consisting of absolute ethanol, isopropanol ormethanol.

In one embodiment of the invention, the pharmaceutically or veterinarilyacceptable carrier of the formulation comprises C₁-C₁₀ alcohols oresters thereof (including acetates, such as ethyl acetate, butyl acetateand the like), C₁₀-C₁₈ saturated fatty acids or esters thereof, C₁₀-C₁₈monounsaturated fatty acids or esters thereof, monoesters or diesters ofaliphatic diacids, glycerol monoesters (e.g. monoglycerides), glyceroldiesters (e.g. diglycerides), glycerol triesters (e.g. triglyceridessuch as triacetin), glycols, glycol ethers, glycol esters or glycolcarbonates, polyethylene glycols of various grades (PEGs) or monoethers,diethers, monoesters or diesters thereof (e.g. diethylene glycolmonoethyl ether), or mixtures thereof.

The liquid carrier vehicle can optionally contain a crystallizationinhibitor including an anionic surfactant, a cationic surfactant, anon-ionic surfactant, an amine salt, an amphoteric surfactant orpolyvinylpyrrolidone, polyvinyl alcohols, copolymers of vinyl acetateand vinylpyrrolidone, 2-pyrrolidone including N-methylpyrrolidone (NMP),dimethylsulfoxide, polyethylene glycols, benzyl alcohol, mannitol,glycerol, sorbitol, polyoxyethylenated sorbitan esters; lecithin, sodiumcarboxymethylcellulose, solvents as defined herein that can inhibit theformation of crystals, and acrylic derivatives such acrylates ormethacrylates as well as other polymers derived from acrylic monomers,or a mixture of these crystallization inhibitors.

Spot-on formulations may be prepared by dissolving the activeingredients into the pharmaceutically or veterinary acceptable vehicle.Alternatively, the spot-on formulation can be prepared by encapsulationof the active ingredient to leave a residue of the therapeutic agent onthe surface of the animal. These formulations will vary with regard tothe weight of the therapeutic agent in the combination depending on thespecies of host animal to be treated, the severity and type of infectionand the body weight of the host.

Dosage forms may contain from about 0.5 mg to about 5 g of an activeagent. In one embodiment of the dosage form, the dosage is from about 1mg to about 500 mg of an active agent, typically about 25 mg, about 50mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg, about 500mg, about 600 mg, about 800 mg, or about 1000 mg.

In one embodiment of the invention, the active agent is present in theformulation at a concentration of about 0.05% to about 50%weight/volume. In other embodiments, the active agent may be present inthe formulation at a concentration of about 0.1% to about 30%, about0.5% to about 20% (w/v) or about 1% to about 10% (w/v). In anotherembodiment of the invention, the active agent is present in theformulation as a concentration from about 0.1 to 2% weight/volume. Inyet another embodiment of the invention, the active agent is present inthe formulation as a concentration from about 0.25 to about 1.5%weight/volume. In still another embodiment of the invention, the activeagent is present in the formulation as a concentration about 1%weight/volume.

In a particular advantageous embodiment of the invention, the dose ofthe inventive compounds is about 0.1 mg/kg to about 100 mg/kg. In otherembodiments, the dose of the inventive compounds is about 0.5 mg/kg toabout 70 mg/kg, about 0.5 mg/kg to about 50 mg/kg or about 0.5 mg/kg toabout 30 mg/kg. In other preferred embodiments, the dose is 0.5 mg/kg toabout 30 mg/kg, 0.5 mg/kg to about 20 mg/kg or 0.5 mg/kg to about 10mg/kg. More typically, in some embodiments the dose of the activecompounds is about 0.1 mg/kg to 5 mg/kg, 0.1 mg/kg to about 3 mg/kg, orabout 0.1 mg/kg to 1.5 mg/kg. In still other embodiments of theinvention, the dose may be as low as 0.1 mg/kg (0.02 mg/ml), about 0.2mg/kg (0.04 mg/ml), about 0.3 mg/kg (0.06 mg/ml), about 0.4 mg/kg (0.08mg/ml), about 0.5 mg/kg (0.1 mg/ml), about 0.6 mg/kg (0.12 mg/ml), about0.7 mg/kg (0.14 mg/ml), about 0.8 mg/kg (0.16 mg/ml), about 0.9 mg/kg(0.18 mg/ml), about 1.0 mg/kg (0.2 mg/ml).

Another embodiment of the invention is directed toward a method oftreating endoparasitic infestation or infection in an animal, comprisingadministering an effective amount of the compound of the invention tothe animal in need thereof. The compounds of the invention have beenshown to have superior efficacy against endoparasites, and in particularagainst parasites that are resistant to active agents of the macrocycliclactone class.

For example, a compound of the invention has been shown to have superiorefficacy against ivermectin-resistant endoparasites in sheep. FIG. 2shows that a compound of the invention (compound 3.024) administered ata dosage of 1.5 mg/kg or 3 mg/kg orally had greater than 95% efficacyagainst ivermectin-resistant strains of Haemonchus contortus, Ostertagiacircumcincta and Trichostrongylus columbriformis. In contrast,ivermectin administered orally at a dose of 0.2 mg/kg was almostcompletely inactive against Haemonchus contortus, less than 30%effective against Ostertagia circumcincta and less than 60% effectiveagainst Trichostrongylus columbriformis. It is surprising that thecompounds of the invention have superior efficacy against endoparasitesthat are resistant to ivermectin, which is one of the most potent activeagents known against endo- and ectoparasites.

Accordingly, in another embodiment, the invention provides a method fortreating an endoparasitic infestation or infection in an animal,comprising administering an effective amount of an anthelmintic compoundof the invention in combination with an effective amount of activatorsof invertebrate GABA receptors including an avermectin or milbemycin tothe animal in need thereof. Avermectins that may be used in combinationwith the compounds of the invention include, but are not limited toabamectin, dimadectin, doramectin, emamectin, eprinomectin, ivermectin,latidectin, lepimectin, and selamectin Milbemycins compounds that may beused in combination with the compounds of the invention include, but arenot limited to, milbemectin, milbemycin D, moxidectin and nemadectin.Also included are the 5-oxo and 5-oxime derivatives of said avermectinsand milbemy cins.

In one embodiment, the compounds and compositions of the invention maybe used for treating endoparasiticidal infection or infestation anendoparasite including, but not limited to, Anaplocephala(Anoplocephala), Ancylostoma, Anecator, Ascaris, Brugia, Bunostomum,Capillaria, Chabertia, Cooperia, Cyathostomum, Cylicocyclus,Cylicodontophorus, Cylicostephanus, Craterostomum, Dictyocaulus,Dipetalonema, Dipylidium, Dirofilaria, Dracunculus, Echinococcus,Enterobius, Fasciola, Filaroides, Habronema, Haemonchus, Metastrongylus,Moniezia, Necator, Nematodirus, Nippostrongylus, Oesophagostumum,Onchocerca, Ostertagia, Oxyuris, Parascaris, Schistosoma, Strongylus,Taenia, Toxocara, Strongyloides, Toxascaris, Trichinella, Trichuris,Trichostrongylus, Triodontophorus, Uncinaria, Wuchereria, andcombinations thereof.

In a particularly preferred embodiment of the invention, the compoundsand compositions of the invention are used to treat or prevent aninfection by Dirofilaria immitis. In another embodiment the compoundsand compositions of the invention are used to treat or prevent aninfection by Dirofilaria repens.

In another embodiment of the invention, the helminth is Haemonchuscontortus, Ostertagia circumcincta, Trichostrongylus axei,Trichostrongylus colubriformis, Cooperia curticei, Nematodirus battusand combinations thereof.

Another embodiment of the invention is directed toward a method oftreating ectoparasitic infestation or infection in an animal in needthereof which comprises administering an effective amount of thecompound of the invention to the animal in need thereof.

In one embodiment, the infection or infestation is caused by fleas,ticks, mites, mosquitoes, flies, lice, blowfly and combinations thereof.

In still another embodiment, invention provides a method for treating anectoparasitic infestation or infection in an animal, comprisingadministering an effective amount of an anthelmintic compound of theinvention in combination with an effective amount of an avermectin ormilbemycin active agent to the animal in need thereof.

In certain embodiments, the compounds of the invention may be used toprotect plants and crops. In other embodiments, the compounds may beused to treat environmental surfaces and structures.

The compounds of formula (I) or their salts can be employed as such orin the form of their preparations (formulations) as combinations withother active substances, such as, for example, insecticides,attractants, sterilants, acaricides, nematicides, and with growthregulators.

Bactericides include, but are not limited to, bronopol, dichlorophen,nitrapyrin, nickel dimethyldithiocarbamate, kasugamycin, octhilinone,furancarboxylic acid, oxytetracycline, probenazole, streptomycin,tecloftalam, copper sulphate and other copper preparations.

Insecticides/acaricides/nematicides include those compounds mentioned inU.S. Pat. Nos. 7,420,062 and 7,001,903, U.S. Patent publication2008/0234331, each incorporated herein by reference, the literatureknown to the person skilled in the art, and the compounds classified byIRAC (Insecticide Resistance Action Committee). Examples ofinsecticides/acaricides/nematicides include, but are limited to,carbamates; triazemate; organophosphates; cyclodiene organochlorines;phenylpyrazoles; DDT; methoxychlor; pyrethroids; pyrethrins;neonicotinoids; nicotine; bensultap; cartap hydrochloride; nereistoxinanalogues; spinosyns; avermectins and milbemycins; juvenile hormoneanalogues; fenoxycarb; fenoxycarb; alkyl halides; chloropicrin; sulfurylfluoride; cryolite; pymetrozine; flonicamid; clofentezine; hexythiazox;etoxazole; Bacillus sphaericus; diafenthiuron; organotin miticides;propargite; tetradifon; chlorfenapyr; DNOC; benzoylureas; buprofezin;cyromazine; diacylhydrazines; azadirachtin; amitraz; hydramethylnon;acequinocyl; fluacrypyrim; METI acaricides; rotenone; indoxacarb;metaflumizone; tetronic acid derivatives; aluminium phosphide; cyanide;phosphine; bifenazate; fluoroacetate; P450-dependent monooxygenaseinhibitors; esterase inhibitors; diamides; benzoximate; chinomethionat;dicofol; pyridalyl; borax; tartar emetic; fumigants, such as methylbromide; ditera; clandosan; sincocin.

The compounds of formula (I) can be formulated in various ways,depending on the prevailing biological and/or chemico-physicalparameters. Examples of possible formulations which are suitable are:wettable powders (WP), water-soluble powders (SP), water-solubleconcentrates, emulsifiable concentrates (EC), emulsions (EW) such asoil-in-water and water-in-oil emulsions, sprayable solutions, suspensionconcentrates (SC), dispersions on an oil or water basis, solutions whichare miscible with oil, capsule suspensions (CS), dusts (DP),seed-dressing products, granules for broadcasting and soil application,granules (GR) in the form of microgranules, spray granules, coatedgranules and adsorption granules, water-dispersible granules (WG),water-soluble granules (SG), ULV formulations, microcapsules and waxes.

Solid state forms of the compounds of formula (I) can be prepared bymethods known in the art, e.g. Byrn et al., “Solid-State Chemistry ofDrugs”, 2^(nd) Edition, SSCI Inc., (1999); Glusker et al., “CrystalStructure Analysis—A Primer”, 2^(nd) Edition, Oxford University Press,(1985).

The formulations mentioned can be prepared in a manner known per se, forexample by mixing the active compounds with at least one solvent ordiluent, emulsifier, dispersant and/or binder or fixative, waterrepellent and optionally one or more of a desiccant, UV stabilizer, acolorant, a pigment and other processing auxiliaries.

These individual formulation types are known in principle and described,for example, in: Winnacker-Küchler, “Chemische Technologie” [ChemicalTechnology], Volume 7, C. Hauser Verlag, Munich, 4th Edition 1986; Wadevan Valkenburg, “Pesticide Formulations”, Marcel Dekker, N. Y., 1973; K.Martens, “Spray Drying Handbook”, 3rd Ed. 1979, G. Goodwin Ltd. London.

The necessary formulation auxiliaries such as inert materials,surfactants, solvents and other additives are also known and described,for example, in: Watkins, “Handbook of Insecticide Dust Diluents andCarriers”, 2nd Ed., Darland Books, Caldwell N.J.; H. v. Olphen,“Introduction to Clay Colloid Chemistry”, 2nd Ed., J. Wiley & Sons,N.Y.; C. Marsden, “Solvents Guide”, 2nd Ed., Interscience, N. Y. 1963;McCutcheon's “Detergents and Emulsifiers Annual”, MC Publ. Corp.,Ridgewood N.J.; Sisley and Wood, “Encyclopedia of Surface ActiveAgents”, Chem. Publ. Co. Inc., N.Y. 1964; Schonfeldt,“Grenzflächenaktive Äthylenoxidaddukte” [Surface-active ethylene oxideadducts], Wiss. Verlagsgesell., Stuttgart 1976; Winnacker-Küchler,“Chemische Technologie” [Chemical Technology], Volume 7, C. HauserVerlag, Munich, 4th Ed. 1986.

Wettable powders are preparations which are uniformly dispersible inwater and which, besides the compounds of formula (I), also compriseionic and/or nonionic surfactants (welters, dispersants), for example,polyoxyethylated alkylphenols, polyoxyethylated fatty alcohols,polyoxyethylated fatty amines, fatty alcohol polyglycol ether sulfates,alkanesulfonates or alkylbenzenesulfonates, sodium lignosulfonate,sodium 2,2′-dinaphthylmethane-6,6′-disulfonate, sodiumdibutylnaphthalenesulfonate or else sodium oleoylmethyltaurinate, inaddition to a diluent or inert substance. To prepare the wettablepowders, the compounds of formula (I) are, for example, ground finely inconventional apparatuses such as hammer mills, blower mills and air-jetmills and mixed with the formulation auxiliaries, either concomitantlyor thereafter.

Emulsifiable concentrates are prepared, for example, by dissolving thecompounds of formula (I) in an organic solvent, for example butanol,cyclohexanone, dimethylformamide, xylene or else higher-boilingaromatics or hydrocarbons or mixtures of these, with addition of one ormore ionic and/or nonionic surfactants (emulsifiers). Emulsifiers whichcan be used are, for example: calcium salts of alkylarylsulfonic acids,such as calcium dodecylbenzenesulfonate or nonionic emulsifiers, such asfatty acid polyglycol esters, alkylaryl polyglycol ethers, fatty alcoholpolyglycol ethers, propylene oxide/ethylene oxide condensates, alkylpolyethers, sorbitan esters such as sorbitan fatty acid esters orpolyoxyethylene sorbitan esters such as polyoxyethylene sorbitan fattyacid esters.

Dusts are obtained by grinding the active substance with finely dividedsolid substances, for example talc or natural clays, such as kaolin,bentonite or pyrophyllite, or diatomaceous earth.

Suspension concentrates may be water- or oil-based. They can beprepared, for example, by wet grinding by means of commerciallyavailable bead mills, if appropriate with addition of surfactants, asthey have already been mentioned above for example in the case of theother formulation types.

Emulsions, for example oil-in-water emulsions (EW), can be prepared forexample by means of stirrers, colloid mills and/or static mixtures usingaqueous organic solvents and, if appropriate, surfactants as they havealready been mentioned above for example in the case of the otherformulation types.

Granules can be prepared either by spraying the compounds of formula (I)onto adsorptive, granulated inert material or by applying activesubstance concentrates onto the surface of carriers such as sand,kaolinites or of granulated inert material, by means of binders, forexample polyvinyl alcohol, sodium polyacrylate or alternatively mineraloils. Suitable active substances can also be granulated in the mannerwhich is conventional for the production of fertilizer granules, ifdesired in a mixture with fertilizers.

Water-dispersible granules are prepared, as a rule, by the customaryprocesses such as spray-drying, fluidized-bed granulation, diskgranulation, mixing in high-speed mixers and extrusion without solidinert material. To prepare disk, fluidized-bed, extruder and spraygranules, see, for example, processes in “Spray-Drying Handbook” 3rd ed.1979, G. Goodwin Ltd., London; J. E. Browning, “Agglomeration”, Chemicaland Engineering 1967, pages 147 et seq.; “Perry's Chemical Engineer'sHandbook”, 5th Ed., McGraw-Hill, New York 1973, p. 8-57. In general, theagrochemical preparations comprise a range selected from the groupconsisting of about 0.1 to about 99% by weight and about 0.1 to about95% by weight, of compounds of formula (I).

The concentration of compounds of formula (I) in wettable powders is,for example, about 10 to about 90% by weight, the remainder to 100% byweight being composed of customary formulation components. In the caseof emulsifiable concentrates, the concentration of compounds of formula(I) can amount to ranges selected from the group consisting of about 1%to about 90% and about 5% to about 80% by weight. Formulations in theform of dusts usually comprise in the range selected from the groupconsisting of about 1% to about 30% by weight of compounds of formula(I) and about 5% to about 20% by weight of compounds of formula (I). Forsprayable solutions comprise a range selected from the group consistingof about 0.05% to about 80% by weight of compounds of formula (I) andabout 2% to about 50% by weight of compounds of formula (I). In the caseof water-dispersible granules, the content of compounds of formula (I)depends partly on whether the compounds of formula (I) are in liquid orsolid form and on which granulation auxiliaries, fillers and the likeare being used. The water-dispersible granules, for example, comprise arange selected from the group consisting of between about 1 and about95% and between about 10% and about 80% by weight.

In addition, the formulations of compounds of formula (I) mentionedcomprise, if appropriate, the adhesives, wetters, dispersants,emulsifiers, penetrants, preservatives, antifreeze agents, solvents,fillers, carriers, colorants, antifoams, evaporation inhibitors, pHregulators and viscosity regulators which are conventional in each case.

Additional pharmaceutically or veterinarily active ingredients may alsobe added to the compositions of the invention. In some embodiments, theadditional active agents may be one or more parasiticidal compoundsincluding acaricides, anthelmintics, endectocides and insecticides.Anti-parasitic agents can include both ectoparasiticisal andendoparasiticidal agents.

Additional pharmaceutical agents that may be included in thecompositions of the invention with the inventive anthelmintic compoundsare well-known in the art (see e.g. Plumb' Veterinary Drug Handbook,5^(th) Edition, ed. Donald C. Plumb, Blackwell Publishing, (2005) or TheMerck Veterinary Manual, 9^(th) Edition, (January 2005)) and include butare not limited to acarbose, acepromazine maleate, acetaminophen,acetazolamide, acetazolamide sodium, acetic acid, acetohydroxamic acid,acetylcysteine, acitretin, acyclovir, albendazole, albuterol sulfate,alfentanil, allopurinol, alprazolam, altrenogest, amantadine, amikacinsulfate, aminocaproic acid, aminopentamide hydrogen sulfate,aminophylline/theophylline, amiodarone, amitriptyline, amlodipinebesylate, ammonium chloride, ammonium molybdenate, amoxicillin,clavulanate potassium, amphotericin B desoxycholate, amphotericin Blipid-based, ampicillin, amprolium, antacids (oral), antivenin,apomorphione, apramycin sulfate, ascorbic acid, asparaginase, aspiring,atenolol, atipamezole, atracurium besylate, atropine sulfate, aurnofin,aurothioglucose, azaperone, azathioprine, azithromycin, baclofen,barbituates, benazepril, betamethasone, bethanechol chloride, bisacodyl,bismuth subsalicylate, bleomycin sulfate, boldenone undecylenate,bromides, bromocriptine mesylate, budenoside, buprenorphine, buspirone,busulfan, butorphanol tartrate, cabergoline, calcitonin salmon,calcitrol, calcium salts, captopril, carbenicillin indanyl sodium,carbimazole, carboplatin, carnitine, carprofen, carvedilol, cefadroxil,cefazolin sodium, cefixime, clorsulon, cefoperazone sodium, cefotaximesodium, cefotetan disodium, cefoxitin sodium, cefpodoxime proxetil,ceftazidime, ceftiofur sodium, ceftiofur, ceftiaxone sodium, cephalexin,cephalosporins, cephapirin, charcoal (activated), chlorambucil,chloramphenicol, chlordiazepoxide, chlordiazepoxide+/−clidinium bromide,chlorothiazide, chlorpheniramine maleate, chlorpromazine,chlorpropamide, chlortetracycline, chorionic gonadotropin (HCG),chromium, cimetidine, ciprofloxacin, cisapride, cisplatin, citratesalts, clarithromycin, clemastine fumarate, clenbuterol, clindamycin,clofazimine, clomipramine, claonazepam, clonidine, cloprostenol sodium,clorazepate dipotassium, clorsulon, cloxacillin, codeine phosphate,colchicine, corticotropin (ACTH), cosyntropin, cyclophosphamide,cyclosporine, cyproheptadine, cytarabine, dacarbazine,dactinomycin/actinomycin D, dalteparin sodium, danazol, dantrolenesodium, dapsone, decoquinate, deferoxamine mesylate, deracoxib,deslorelin acetate, desmopressin acetate, desoxycorticosterone pivalate,detomidine, dexamethasone, dexpanthenol, dexraazoxane, dextran,diazepam, diazoxide (oral), dichlorphenamide, diclofenac sodium,dicloxacillin, diethylcarbamazine citrate, diethylstilbestrol (DES),difloxacin, digoxin, dihydrotachysterol (DHT), diltiazem,dimenhydrinate, dimercaprol/BAL, dimethyl sulfoxide, dinoprosttromethamine, diphenylhydramine, disopyramide phosphate, dobutamine,docusate/DSS, dolasetron mesylate, domperidone, dopamine, doramectin,doxapram, doxepin, doxorubicin, doxycycline, edetate calciumdisodium.calcium EDTA, edrophonium chloride, enalapril/enalaprilat,enoxaparin sodium, enrofloxacin, ephedrine sulfate, epinephrine,epoetin/erythropoietin, eprinomectin, epsiprantel, erythromycin,esmolol, estradiol cypionate, ethacrynic acid/ethacrynate sodium,ethanol (alcohol), etidronate sodium, etodolac, etomidate, euthanasiaagents w/pentobarbital, famotidine, fatty acids (essential/omega),felbamate, fentanyl, ferrous sulfate, filgrastim, finasteride, fipronil,florfenicol, fluconazole, flucytosine, fludrocortisone acetate,flumazenil, flumethasone, flunixin meglumine, fluorouracil (5-FU),fluoxetine, fluticasone propionate, fluvoxamine maleate, fomepizole(4-MP), furazolidone, furosemide, gabapentin, gemcitabine, gentamicinsulfate, glimepiride, glipizide, glucagon, glucocorticoid agents,glucosamine/chondroitin sulfate, glutamine, glyburide, glycerine (oral),glycopyrrolate, gonadorelin, grisseofulvin, guaifenesin, halothane,hemoglobin glutamer-200 (OXYGLOBIN®®), heparin, hetastarch, hyaluronatesodium, hydrazaline, hydrochlorothiazide, hydrocodone bitartrate,hydrocortisone, hydromorphone, hydroxyurea, hydroxyzine, ifosfamide,imidacloprid, imidocarb dipropinate, impenem-cilastatin sodium,imipramine, inamrinone lactate, insulin, interferon alfa-2a (humanrecombinant), iodide (sodium/potassium), ipecac (syrup), ipodate sodium,iron dextran, isoflurane, isoproterenol, isotretinoin, isoxsuprine,itraconazole, ivermectin, kaolin/pectin, ketamine, ketoconazole,ketoprofen, ketorolac tromethamine, lactulose, leuprolide, levamisole,levetiracetam, levothyroxine sodium, lidocaine, lincomycin, liothyroninesodium, lisinopril, lomustine (CCNU), lufenuron, lysine, magnesium,mannitol, marbofloxacin, mechlorethamine, meclizine, meclofenamic acid,medetomidine, medium chain triglycerides, medroxyprogesterone acetate,megestrol acetate, melarsomine, melatonin, meloxican, melphalan,meperidine, mercaptopurine, meropenem, metformin, methadone,methazolamide, methenamine mandelate/hippurate, methimazole, methionine,methocarbamol, methohexital sodium, methotrexate, methoxyflurane,methylene blue, methylphenidate, methylprednisolone, metoclopramide,metoprolol, metronidaxole, mexiletine, mibolerlone, midazolam milbemycinoxime, mineral oil, minocycline, misoprostol, mitotane, mitoxantrone,morphine sulfate, moxidectin, naloxone, mandrolone decanoate, naproxen,narcotic (opiate) agonist analgesics, neomycin sulfate, neostigmine,niacinamide, nitazoxanide, nitenpyram, nitrofurantoin, nitroglycerin,nitroprusside sodium, nizatidine, novobiocin sodium, nystatin,octreotide acetate, olsalazine sodium, omeprozole, ondansetron, opiateantidiarrheals, orbifloxacin, oxacillin sodium, oxazepam, oxibutyninchloride, oxymorphone, oxytretracycline, oxytocin, pamidronate disodium,pancreplipase, pancuronium bromide, paromomycin sulfate, parozetine,pencillamine, general information penicillins, penicillin G, penicillinV potassium, pentazocine, pentobarbital sodium, pentosan polysulfatesodium, pentoxifylline, pergolide mesylate, phenobarbital,phenoxybenzamine, pheylbutazone, phenylephrine, phenypropanolamine,phenytoin sodium, pheromones, parenteral phosphate, phytonadione/vitaminK-1, pimobendan, piperazine, pirlimycin, piroxicam, polysulfatedglycosaminoglycan, ponazuril, potassium chloride, pralidoxime chloride,prazosin, prednisolone/prednisone, primidone, procainamide,procarbazine, prochlorperazine, propantheline bromide, propionibacteriumacnes injection, propofol, propranolol, protamine sulfate,pseudoephedrine, psyllium hydrophilic mucilloid, pyridostigmine bromide,pyrilamine maleate, pyrimethamine, quinacrine, quinidine, ranitidine,rifampin, s-adenosyl-methionine (SAMe), saline/hyperosmotic laxative,selamectin, selegiline/l-deprenyl, sertraline, sevelamer, sevoflurane,silymarin/milk thistle, sodium bicarbonate, sodium polystyrenesulfonate, sodium stibogluconate, sodium sulfate, soduim thiosulfate,somatotropin, sotalol, spectinomycin, spironolactone, stanozolol,streptokinase, streptozocin, succimer, succinylcholine chloride,sucralfate, sufentanil citrate, sulfachlorpyridazine sodium,sulfadiazine/trimethroprim, sulfamethoxazole/trimethoprim,sulfadimentoxine, sulfadimethoxine/ormetoprim, sulfasalazine, taurine,tepoxaline, terbinafline, terbutaline sulfate, testosterone,tetracycline, thiacetarsamide sodium, thiamine, thioguanine, thiopentalsodium, thiotepa, thyrotropin, tiamulin, ticarcilin disodium,tiletamine/zolazepam, tilmocsin, tiopronin, tobramycin sulfate,tocainide, tolazoline, telfenamic acid, topiramate, tramadol,trimcinolone acetonide, trientine, trilostane, trimepraxine tartratew/prednisolone, tripelennamine, tylosin, urdosiol, valproic acid,vanadium, vancomycin, vasopressin, vecuronium bromide, verapamil,vinblastine sulfate, vincristine sulfate, vitamin E/selenium, warfarinsodium, xylazine, yohimbine, zafirlukast, zidovudine (AZT), zincacetate/zinc sulfate, zonisamide and mixtures thereof.

In one embodiment of the invention, arylpyrazole compounds such asphenylpyrazoles, known in the art may be combined with the anthelminticcompounds of the invention. Examples of such arylpyrazole compoundsinclude but are not limited to those described in U.S. Pat. Nos.6,001,384; 6,010,710; 6,083,519; 6,096,329; 6,174,540; 6,685,954 and6,998,131 (all of which are incorporated herein by reference, eachassigned to Merial, Ltd., Duluth, Ga.). On particularly preferredarylpyrazole compound is fipronil.

In another embodiment of the invention, one or more macrocyclic lactonesor lactams, which act as an acaricide, anthelmintic agent and/orinsecticide, can be added to the compositions of the invention.

The macrocyclic lactones include, but are not limited to, avermectinssuch as abamectin, dimadectin, doramectin, emamectin, eprinomectin,ivermectin, latidectin, lepimectin, selamectin and ML-1,694,554, andmilbemycins such as milbemectin, milbemycin D, moxidectin andnemadectin. Also included are the 5-oxo and 5-oxime derivatives of saidavermectins and milbemycins. Examples of combinations of arylpyrazolecompounds with macrocyclic lactones include but are not limited to thosedescribed in U.S. Pat. Nos. 6,426,333; 6,482,425; 6,962,713 and6,998,131 (all incorporated herein by reference—each assigned to Merial,Ltd., Duluth, Ga.).

The macrocyclic lactone compounds are known in the art and can easily beobtained commercially or through synthesis techniques known in the art.Reference is made to the widely available technical and commercialliterature. For avermectins, ivermectin and abamectin, reference may bemade, for example, to the work “Ivermectin and Abamectin”, 1989, by M.H. Fischer and H. Mrozik, William C. Campbell, published by SpringerVerlag., or Albers-Schonberg et al. (1981), “Avermectins StructureDetermination”, J. Am. Chem. Soc., 103, 4216-4221. For doramectin,“Veterinary Parasitology”, vol. 49, No. 1, July 1993, 5-15 may beconsulted. For milbemycins, reference may be made, inter alio, to DaviesH. G. et al., 1986, “Avermectins and Milbemycins”, Nat. Prod. Rep., 3,87-121, Mrozik H. et al., 1983, Synthesis of Milbemycins fromAvermectins, Tetrahedron Lett., 24, 5333-5336, U.S. Pat. No. 4,134,973and EP 0 677 054, both incorported herein by reference.

Macrocyclic lactones are either natural products or are semi-syntheticderivatives thereof. The structure of the avermectins and milbemycinsare closely related, e.g., by sharing a complex 16-membered macrocycliclactone ring. The natural product avermectins are disclosed in U.S. Pat.No. 4,310,519 and the 22,23-dihydro avermectin compounds are disclosedin U.S. Pat. No. 4,199,569. Mention is also made of U.S. Pat. Nos.4,468,390, 5,824,653, EP 0 007 812 A1, U.K. Patent Specification 1 390336, EP 0 002 916, and New Zealand Patent No. 237 086, inter alia, allincorporated herein by reference. Naturally occurring milbemycins aredescribed in U.S. Pat. No. 3,950,360 (incorporated herein by reference)as well as in the various references cited in “The Merck Index” 12^(th)ed., S. Budavari, Ed., Merck & Co., Inc. Whitehouse Station, N.J.(1996). Latidectin is described in the “International NonproprietaryNames for Pharmaceutical Substances (INN)”, WHO Drug Information, vol.17, no. 4, pp. 263-286, (2003). Semisynthetic derivatives of theseclasses of compounds are well known in the art and are described, forexample, in U.S. Pat. Nos. 5,077,308, 4,859,657, 4,963,582, 4,855,317,4,871,719, 4,874,749, 4,427,663, 4,310,519, 4,199,569, 5,055,596,4,973,711, 4,978,677, 4,920,148 and EP 0 667 054, all incorporatedherein by reference.

In another embodiment of the invention, the compositions may include aclass of acaricides or insecticides known as insect growth regulators(IGRs). Compounds belonging to this group are well known to thepractitioner and represent a wide range of different chemical classes.These compounds all act by interfering with the development or growth ofthe insect pests. Insect growth regulators are described, for example,in U.S. Pat. Nos. 3,748,356, 3,818,047, 4,225,598, 4,798,837, 4,751,225,EP 0 179 022 or U.K. 2 140 010 as well as U.S. Pat. Nos. 6,096,329 and6,685,954 (all incorporated herein by reference).

In one embodiment the IGR that may be included in the composition is acompound that mimics juvenile hormone. Examples of juvenile hormonemimics include azadirachtin, diofenolan, fenoxycarb, hydroprene,kinoprene, methoprene, pyriproxyfen, tetrahydroazadirachtin and4-chloro-2(2-chloro-2-methyl-propyl)-5-(6-iodo-3-pyridylmethoxy)pyridazine-3(2H)-one.In a particularly preferred embodiment, the compositions of theinvention comprise methoprene or pyriproxyfen.

In another embodiment, the compositions of the invention may include anIGR compound that is a chitin synthesis inhibitor. Chitin synthesisinhibitors include chlorofluazuron, cyromazine, diflubenzuron,fluazuron, flucycloxuron, flufenoxuron, hexaflumoron, lufenuron,tebufenozide, teflubenzuron, triflumoron, novaluron,1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-(trifluoromethyl)phenylurea,1-(2,6-difluoro-benzoyl)-3-(2-fluoro-4-(1,1,2,2-tetrafluoroethoxy)-phenylureaand 1-(2,6-difluorobenzoyl)-3-(2-fluoro-4-trifluoromethyl)phenylurea.

In yet another embodiment of the invention, adulticide insecticides andacaricides can also be added to the composition of the invention. Theseinclude pyrethrins (which include cinerin I, cinerin II, jasmolin I,jasmolin II, pyrethrin I, pyrethrin II and mixtures thereof) andpyrethroids, and carbamates including, but are not limited to, benomyl,carbanolate, carbaryl, carbofuran, meththiocarb, metolcarb, promacyl,propoxur, aldicarb, butocarboxim, oxamyl, thiocarboxime and thiofanox.

In some embodiments, the compositions of the invention may include oneor more antinematodal agents including, but not limited to, activeagents in the benzimidazoles, imidazothiazoles, tetrahydropyrimidines,and organophosphate class of compounds. In some embodiments,benzimidazoles including, but not limited to, thiabendazole,cambendazole, parbendazole, oxibendazole, mebendazole, flubendazole,fenbendazole, oxfendazole, albendazole, cyclobendazole, febantel,thiophanate and its o,o-dimethyl analogue may be included in thecompositions.

In other embodiments, the compositions may include an imidazothiazolecompounds including, but not limited to, tetramisole, levamisole andbutamisole. In still other embodiments, the compositions of theinvention may include tetrahydropyrimidine active agents including, butnot limited to, pyrantel, oxantel, and morantel. Suitableorganophosphate active agents include, but are not limited to,coumaphos, trichlorfon, haloxon, naftalofos and dichlorvos, heptenophos,mevinphos, monocrotophos, TEPP, and tetrachlorvinphos.

In other embodiments, the compositions may include the antinematodalcompounds phenothiazine and piperazine as the neutral compound or invarious salt forms, diethylcarbamazine, phenols such as disophenol,arsenicals such as arsenamide, ethanolamines such as bephenium, theniumclosylate, and methyridine; cyanine dyes including pyrvinium chloride,pyrvinium pamoate and dithiazanine iodide; isothiocyanates includingbitoscanate, suramin sodium, phthalofyne, and various natural productsincluding, but not limited to, hygromycin B, α-santonin and kainic acid.

In other embodiments, the compositions of the invention may includeantitrematodal agents. Suitable antitrematodal agents include, but arenot limited to, the miracils such as miracil D and mirasan;praziquantel, clonazepam and its 3-methyl derivative, oltipraz,lucanthone, hycanthone, oxamniquine, amoscanate, niridazole, nitroxynil,various bisphenol compounds known in the art including hexachlorophene,bithionol, bithionol sulfoxide and menichlopholan; varioussalicylanilide compounds including tribromsalan, oxyclozanide,clioxanide, rafoxanide, brotianide, bromoxanide and closantel;triclabendazole, diamfenetide, clorsulon, hetolin and emetine.

Anticestodal compounds may also be advantageously used in thecompositions of the invention including, but not limited to, arecolinein various salt forms, bunamidine, niclosamide, nitroscanate,paromomycin and paromomycin II.

In yet other embodiments, the compositions of the invention may includeother active agents that are effective against arthropod parasites.Suitable active agents include, but are not limited to, bromocyclen,chlordane, DDT, endosulfan, lindane, methoxychlor, toxaphene, bromophos,bromophos-ethyl, carbophenothion, chlorfenvinphos, chlorpyrifos,crotoxyphos, cythioate, diazinon, dichlorenthion diemthoate, dioxathion,ethion, famphur, fenitrothion, fenthion, fospirate, iodofenphos,malathion, naled, phosalone, phosmet, phoxim, propetamphos, ronnel,stirofos, allethrin, cyhalothrin, cypermethrin, deltamethrin,fenvalerate, flucythrinate, permethrin, phenothrin, pyrethrins,resmethrin, benzyl benzoate, carbon disulfide, crotamiton,diflubenzuron, diphenylamine, disulfiram, isobornyl thiocyanato acetate,methoprene, monosulfiram, pirenonylbutoxide, rotenone, triphenyltinacetate, triphenyltin hydroxide, deet, dimethyl phthalate, and thecompounds 1,5a,6,9,9a,9b-hexahydro-4a(4H)-dibenzofurancarboxaldehyde(MGK-11),2-(2-ethylhexyl)-3a,4,7,7a-tetrahydro-4,7-methano-1H-isoindole-1,3(2H)dione(MGK-264), dipropyl-2,5-pyridinedicarboxylate (MGK-326) and2-(octylthio)ethanol (MGK-874). In a particularly preferred embodiment,the compositions of the invention will include permethrin in combinationwith the anthelmintic compounds of the invention.

An antiparasitic agent that can be combined with the compound of theinvention to form a composition can be a biologically active peptide orprotein including, but not limited to, depsipeptides, which act at theneuromuscular junction by stimulating presynaptic receptors belonging tothe secretin receptor family resulting in the paralysis and death ofparasites. In one embodiment of the depsipeptide, the depsipeptide isemodepside (see Willson et al., Parasitology, Jan. 2003, 126(Pt1):79-86).

In another embodiment, the compositions of the invention may comprise anactive agent from the neonicotinoid class of pesticides. Theneonicotinoids bind and inhibit insect specific nicotinic acetylcholinereceptors. In one embodiment, the neonicotinoid insecticidal agent thatmay be included in a composition of the invention is imidacloprid.Imidacloprid is a well-known neonicotinoid active agent and is the keyactive ingredient in the topical parasiticide products Advantage®,Advantage® II, K9 Advantix®, and K9 Advantix® II sold by Bayer AnimalHealth. Agents of this class are described, for example, in U.S. Pat.No. 4,742,060 or in EP 0 892 060.

In another embodiment, the compositions of the invention may comprisenitenpyram, another active agent of the neonicotinoid class ofpesticides. Nitenpyram has the following chemical structure and is theactive ingredient in the oral product CAPSTAR™ Tablets sold by NovartisAnimal Health.

In certain embodiments, an insecticidal agent that can be combined withthe compositions of the invention is a semicarbazone, such asmetaflumizone.

In another embodiment of the invention, nodulisporic acid and itsderivatives (a class of known acaricidal, anthelmintic, anti-parasiticand insecticidal agents) may be added to the compositions of theinvention. These compounds are used to treat or prevent infections inhumans and animals and are described, for example, in U.S. Pat. Nos.5,399,582, 5,962,499, 6,221,894 and 6,399,786, all of which are herebyincorporated by reference in their entirety. The compositions mayinclude one or more of the known nodulisporic acid derivatives in theart, including all stereoisomers, such as those described in the patentscited above.

In another embodiment, anthelmintic compounds of the amino acetonitrileclass (AAD) of compounds such as monepantel (ZOLVIX), and the like, maybe added to the compositions of the invention. These compounds aredescribed, for example, in WO 2004/024704 and U.S. Pat. No. 7,084,280(both incorporated by reference); Sager et al., Veterinary Parasitology,2009, 159, 49-54; Kaminsky et al., Nature vol. 452, 13 Mar. 2008,176-181. The compositions of the invention may also includearyloazol-2-yl cyanoethylamino compounds such as those described in U.S.Pat. No. 8,088,801 to Soll et al., which is incorporated herein in itsentirety, and thioamide derivatives of these compounds, as described inU.S. Pat. No. 7,964,621, which is incorporated herein by reference.

The compositions of the invention may also be combined withparaherquamide compounds and derivatives of these compounds, includingderquantel (see Ostlind et al., Research in Veterinary Science, 1990,48, 260-61; and Ostlind et al., Medical and Veterinary Entomology, 1997,11, 407-408). The paraherquamide family of compounds is a known class ofcompounds that include a spirodioxepino indole core with activityagainst certain parasites (see Tet. Lett. 1981, 22, 135; J. Antibiotics1990, 43, 1380, and J. Antibiotics 1991, 44, 492). In addition, thestructurally related marcfortine family of compounds, such asmarcfortines A-C, are also known and may be combined with theformulations of the invention (see J. Chem. Soc.—Chem. Comm. 1980, 601and Tet. Lett. 1981, 22, 1977). Further references to the paraherquamidederivatives can be found, for example, in WO 91/09961, WO 92/22555, WO97/03988, WO 01/076370, WO 09/004432, U.S. Pat. No. 5,703,078 and U.S.Pat. No. 5,750,695, all of which are hereby incorporated by reference intheir entirety.

In another particularly preferred embodiment, the compositions of theinvention may advantageously include one or more compounds of theisoxazoline class of compounds. These active agents are described in WO2007/079162, WO 2007/075459 and US 2009/0133319, WO 2007/070606 and US2009/0143410, WO 2009/003075, WO 2009/002809, WO 2009/024541, U.S. Pat.No. 7,662,972, WO 2008/122375, WO 2010/003877, WO 2010/003923, WO2009/025983, WO 2008/150393, WO 2008/154528, WO 2009/045999, WO2009/051956, WO 2009/126668, WO 2009/0259832, WO 2008/109760, US2009/0156643, US 2010/0144797, US 2010/0137612, US 2011/009438 and WO2011/075591, all of which are incorporated herein by reference in theirentirety.

Where appropriate the anthelmintic, parasiticidal and insecticial agentmay also be selected from the group of compounds described above assuitable for agrochemical use.

In general, the additional active agent is included in a dose of betweenabout 0.1 μg and about 500 mg. In some embodiments, the additionalactive agent may be present in a dose of about 1 mg to about 500 mg,about 1 mg to about 300 mg, or about 1 mg to about 100 mg. In otherembodiments, the additional active agent may be present in a dose ofabout 1 mg to about 50 mg or about 1 mg to about 20 mg. In otherembodiment of the invention, the additional active agent is included ina dose of about 1 μg to about 10 mg.

In another embodiment of the invention, the additional active agent isincluded in a dose of about 5 μg/kg to about 50 mg/kg. In otherembodiments, the additional active agent may be included in a dose ofabout 5 μg/kg to about 30 mg/kg, about 5 μg/kg to about 20 mg/kg orabout 5 μg/kg to about 10 mg/kg. In still other embodiments, theadditional active agent may be included in a dose of about 10 μg/kg toabout 1 mg/kg or about 50 μg/kg to about 500 μg/kg of weight of theanimal. In yet another embodiment of the invention, the additionalactive agent is included in a dose between about 0.1 mg/kg to about 10mg/kg of weight of animal. In still another embodiment of the invention,the additional active agent is included in a dose between about 0.5mg/kg to 50 mg/kg.

The proportions, by weight, of the aryloazol-2-yl-cyanoethylaminocompound and the additional active agent are for example between about5/1 and about 10,000/1. However, one of ordinary skill in the art wouldbe able to select the appropriate ratio ofaryloazol-2-yl-cyanoethylamino compound and the additional active agentfor the intended host and use thereof.

Processes of Preparation

Another aspect of the invention is the process of making the novelanthelmintic compounds of the invention. The compounds of the inventionmay be prepared according to the processes described herein or by theapplication or adaptation of known methods (i.e. methods heretofore usedor described in the chemical literature). For example, in someembodiments, the compounds of the invention may be prepared by methodsdescribed in WO 2009/077527 A1, WO 2010/115688 A1, WO 2010/146083 A1 andEP 2 468 096 A1 (all incorporated herein by reference), or by adaptationof methods described in these publications.

LIST OF ABBREVIATIONS

-   AIBN azobisisobutyronitrile-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl-   BSA bovine serum albumin-   BOC ter t-butoxy carbonyl-   dba dibenzylidineacetone-   CDI 1,1′-carbonyl diimidazole-   CI chemical ionization-   DEGMME diethylene glycol monomethyl ether-   DIAD diisopropylazodicarboxylate-   DIEA diisopropylethylamine-   DMF N,N-dimethylformamide-   DMSO dimethylsulfoxide-   DPPA diphenylphosphoryl azide-   EDAC.HCl 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide    hydrochloride-   ES electrospray-   EtOAc ethyl acetate-   HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5    b]pyridinium 3-oxide hexafluorophosphate-   HBSS Hank's Balanced Salt Solution-   HOBt 1-hydroxybenzotriazole-   NBS N-bromosuccinimde-   NMM N-methylmorpholine-   POM polyoxymethylene (formaldehyde polymer)-   TBAF tert-butyl ammonium fluoride-   TBHP tert-butyl hydrogen peroxide-   TFA trifluoroacetic acid-   TFAA trifluoroacetic acid anhydride-   THF tetrahydrofuran

Example 1 Synthesis of Common Intermediate (Acid #1)

Step 1. Formation of4-(4-cyano-3-trifluoromethyl-phenylamino)-cyclohexanol

The aryl fluoride (2 g, 10.6 mmol) was placed in a 100 ml round-bottomedflask and stirred in 20 ml acetonitrile at room temperature. Potassiumcarbonate (3.3 g, 23.9 mmol, 2.2 eq) and 1,4-trans-amino-cyclohexanol(1.34 g, 11.6 mmol, 1.1 eq) were added and the mixture was then heatedat 90° C. overnight. The mixture was cooled to room temperature and thenconcentrated under vacuum. The crude material was purified by silica gelchromatography using 20-40% ethyl acetate in petroleum ether to elute.The product-containing fractions were combined and concentrated undervacuum to provide 1 g (33%) of the desired aniline as a yellow oil. (ES,m/z): [M+H]⁺ 285.0; ¹H NMR (300 MHz, DMSO): δ 8.04 (d, J=9.3 Hz, 1H),7.42 (d, J=7.8 Hz, 1H), 7.06 (d, J=1.8 Hz, 1H), 6.82-6.86 (m, 1H), 4.59(d, J=4.2 Hz, 1H), 3.39-3.49 (m, 2H), 1.78-1.94 (m, 4H), 1.18-1.32 (m,4H).

Step 2. Formation of[4-(4-cyano-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acidtert-butyl ester

In a 250 ml round-bottomed flask under nitrogen, a solution of4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (1 g, 3.5 mmol)in 20 ml of THF was cooled using an external ice bath. Sodium hydride(254 mg, 10.6 mmol, 3 eq) was then added and the mixture was stirred at˜0-5° C. for 20 minutes before adding the tert-butyl-2-bromoacetate (700mg, 3.6 mmol, 1 eq). The solution was allowed to warm to roomtemperature while stirring for 2 hours. The reaction was then dilutedusing 50 ml of water. The mixture was then extracted with 3×50 ml ofethyl acetate. The organic layers were combined, dried over sodiumsulfate, filtered, and concentrated under vacuum. The crude material waspurified by silica gel chromatography using 10-20% ethyl acetate inpetroleum ether to elute. The product-containing fractions were combinedand concentrated under vacuum to provide 0.5 g (36%) of the desiredester as an off-white powder. (ES, m/z): [M+H]⁺ 399.0. ¹H NMR (300 MHz,CDCl₃): δ 7.53 (d, J=8.7 Hz, 1H), 6.83 (s, 1H), 6.65-6.83 (t, J=6.9 Hz,1H), 4.01 (s, 2H), 3.36-3.42 (m, 2H), 2.12-2.15 (m, 4H), 1.49 (s, 9H),1.24-1.32 (m, 4H).

Step 3. Formation of[4-(4-cyano-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid

To a solution of tert-butyl2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetate (150mg, 0.38 mmol) in dichloromethane (20 ml) was added trifluoroacetic acid(500 mg, 4.4 mmol, 2.6 eq). The resulting solution was stirred for 2hours at room temperature and then concentrated under vacuum. Theresidue was dissolved in water (10 ml) and then extracted with n-butanol(2×50 ml). The organic layers were combined, dried over sodium sulfate,filtered, and concentrated under vacuum. The crude material was purifiedby silica gel chromatography using 3% methanol in dichloromethane toelute. The product-containing fractions were combined and concentratedunder vacuum to afford 41.7 mg (32%) of2-(4-(4-cyano-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acidas a light yellow oil. (ES, m/z):

[M+H]⁺ 343.1; ¹H NMR (300 MHz, CD₃OD): δ 7.58 (d, J=8.7 Hz, 1H), 6.94(d, J=2.1 Hz, 1H), 6.79-6.83 (dd, J=2.1 Hz, 8.7 Hz, 1H), 4.12 (s, 2H),3.35-3.51 (m, 2H), 2.04-2.20 (m, 4H), 1.24-1.53 (m, 4H).

Example 2 Synthesis of Common Intermediate (Acid #2)

Step 1. Formation of4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol

The aryl fluoride (500 mg, 2.4 mmol) was placed in a 100 mlround-bottomed flask and stirred in 10 ml DMSO at room temperature.Potassium carbonate (661 mg, 4.75 mmol, 2 eq) and1,4-trans-amino-cyclohexanol (413 mg, 3.59 mmol, 1.5 eq) were added andthe mixture was then heated at 90° C. overnight. The mixture was cooledto room temperature and then partitioned between water and ethyl acetate(3×80 ml). The organic layers were combined, washed with saturatedaqueous sodium chloride, dried over sodium sulfate, filtered, andconcentrated under vacuum to provide 400 mg (55%) of the desired anilineas a yellow solid. On both the 10 g and 50 g scale, similar reactionconditions (using acetonitrile as the solvent) provided a 76% yield ofthe desired product.

Step 2. Formation of[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acidtert-butyl ester

In a 250 ml round-bottomed flask under nitrogen, a solution of4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexanol (10 g, 33 mmol)in 150 ml of THF was cooled using an external ice bath. Sodium hydride(3.65 g, 152 mmol, 3 eq) was then added and the mixture was stirred at˜0° C. for 30 minutes before adding the tert-butyl-2-bromoacetate (9.6g, 49.2 mmol, 1.5 eq). The solution was allowed to warm to roomtemperature while stirring overnight. The reaction was then dilutedusing 500 ml of ice-water. The mixture was then extracted with 3×200 mlof ethyl acetate. The organic layers were combined, dried over sodiumsulfate, filtered, and concentrated under vacuum. The crude material waspurified by silica gel chromatography using 10% ethyl acetate inpetroleum ether to elute. The product-containing fractions were combinedand concentrated under vacuum to provide 5 g (36%) of the desired esteras a yellow oil. Repeating this reaction on a larger scale yielded 51%of the desired product.

Step 3. Formation of[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid

To a solution of tert-butyl2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetate (1 g,2.39 mmol) in dichloromethane (30 ml) was added trifluoroacetic acid (5ml). The resulting solution was stirred for 2 hours at room temperatureand then concentrated under vacuum. The resulting solution was dilutedwith dichloromethane (200 ml), washed with water (100 ml), dried overanhydrous sodium sulfate, filtered, and then concentrated under vacuumto afford 800 mg (92%) of2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acidas yellow oil. ¹H NMR (300 MHz, DMSO): δ 12.5 (broad s, 1H), 8.07 (d,J=9.3 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 6.87 (dd, J=2.4 Hz,9.3 Hz, 1H), 4.03 (s, 2H), 3.32-3.46 (m, 2H), 1.91-2.03 (m, 4H),1.17-1.41 (m, 4H).

Example 3 Synthesis of Common Intermediate (Amine #1)

Step 1. Formation of tert-butyl4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate

To a solution of 4-fluoro-1-nitro-2-(trifluoromethyl)benzene (5 g, 24mmol) in DMSO (50 ml) was added tert-butyl4-aminopiperidine-1-carboxylate (4.78 g, 23.9 mmol, 1 eq.) and potassiumcarbonate (9.9 g, 72 mmol, 3 eq.). The resulting mixture was stirredwith heating overnight at 100° C. (oil bath) and then diluted with water(300 ml). The solids were collected by filtration to afford tert-butyl44-[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate asa yellow powder (8 g, 86%); (ES, m/z): [M+H]⁺ 390.0; ¹H NMR (300 MHz,DMSO-d6): δ 8.06 (d, J=9.3 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.08 (d,J=2.1 Hz, 1H), 6.89 (dd, J=2.4, 9.3 Hz, 1H), 3.87 (d, J=13.5 Hz, 2H),3.68 (m, 1H), 2.95 (m, 2H), 2.54 (s, 0.6H), 1.89 (m, 2H), 1.39 (s, 9H),1.28 (m, 2H).

Step 2. Formation ofN-[4-nitro-3-(trifluoromethyl)phenyl]piperidin-4-amine (Amine #1)

To a solution of tert-butyl4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate (1g, 2.6 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid(3 ml). The solution was stirred for 2 hours at room temperature andthen concentrated under vacuum. The crude material was diluted withwater (50 ml), adjusted pH to 9 with sodium bicarbonate (saturatedaqueous), and extracted with dichloromethane (3×100 ml). The organiclayers were combined and dried over anhydrous sodium sulfate, filtered,and concentrated under vacuum to affordN-[4-nitro-3-(trifluoromethyl)phenyl]piperidin-4-amine as a yellowpowder (800 mg, crude); (ES, m/z): [M+H]⁺ 290.1; ¹H NMR (300 MHz,DMSO-d6): δ 8.08 (d, J=9.0 Hz, 1H), 7.20-7.80 (br s), 7.60 (d, J=7.8 Hz,1H), 7.11 (d, J=2.4 Hz, 1H), 6.91 (dd, J=2.4, 9.0 Hz, 1H), 3.70 (m, 1H),3.22 (d, J=12.6 Hz, 2H), 2.91 (dd, J=10.5, 11.4 Hz, 2H), 1.99 (d, J=11.4Hz, 2H), 1.52 (m, 2H).

Example 4 Synthesis of Common Intermediate (Amine #2)

Step 1. Formation of tert-butyl4-[[4-cyano-3-trifluoromethyl)phenyl]amino]piperidine-1-carboxylate

To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (5 g, 26mmol,) in DMSO (50 ml) was added tert-butyl4-aminopiperidine-1-carboxylate (5.3 g, 26.5 mmol, 1 eq.) and potassiumcarbonate (7.3 g, 52.8 mmol, 2 eq.). The resulting solution was stirredwith heating overnight at 100° C. (oil bath). The resulting solution wasdiluted with of ethyl acetate (300 ml) and washed with sodium chloride(sat., 300 ml). The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum to give a residue,which was applied onto a silica gel column and eluted with ethyl acetateto afford tert-butyl4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate asa white powder (5 g, 51%). (ES, m/z): [M+H]⁺ 370.1.

Step 2. Formation ofN-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-amine (Amine #2)

To a solution of tert-butyl4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]piperidine-1-carboxylate(150 mg, 0.41 mmol) in dichloromethane (4 mL) was added trifluoroaceticacid (1 ml). The solution was stirred for 2 hours at room temperatureand then concentrated under vacuum. The crude material was diluted with100 ml of EtOAc and washed with sodium bicarbonate (saturated aqueous)and then brine. The organic layer was dried over anhydrous sodiumsulfate, filtered, and concentrated under vacuum. The crude solids wererecrystallized from EtOAc/PE to affordN-[4-cyano-3-(trifluoromethyl)phenyl]piperidin-4-amine as a yellowpowder (93.1 mg, 85% yield); (ES, m/z): [M+H]⁺ 270.1; ¹H NMR (300 MHz,CDCl₃): δ 7.69 (d, J=8.7 Hz, 1H), 7.16 (d, J=7.8 Hz, 1H), 7.03 (d, J=1.2Hz, 1H), 6.85 (dd, J=2.1, 8.7 Hz, 1H), 3.42 (m, 1H), 2.94 (m, 2H), 2.53(m, 2H), 1.82 (d, J=10.2 Hz, 2H), 1.27 (m, 2H).

Example 5 Preparation of Compound 104

Step 1. Formation of 1-naphthalen-2-yl-piperazine hydrochloride

A solution of naphthalen-2-amine (2 g, 14 mmol) andbis(2-chloroethyl)amine hydrochloride (2.51 g, 14.1 mmol, 1 eq) indiethylene glycol monoethyl ether (3 mL) was stirred overnight at 149°C. (oil bath). The resulting solution was diluted with methanol (2 ml).The crude product was re-crystallized from diethyl ether to afford1-(naphthalen-2-yl)piperazine hydrochloride as a yellow solid (2 g,58%). (ES, m/z): [M+H]⁺ 213.0

Step 2. Formation of1-(4-(naphthalen-2-yl)piperazin-1-yl)-2-(4-(4-nitro-3-(trifluoromethyl)phenyl amino)cyclohexyloxy)ethanone (#14)

To a solution of 1-(naphthalen-2-yl)piperazine hydrochloride (100 mg,0.40 mmol) in dichloromethane (20 ml) was added2-(4-(4-nitro-3-trifluoromethyl)phenylamino)cyclohexyloxy)acetic acid(145 mg, 0.40 mmol, 1 eq), HATU (153 mg, 0.40 mmol, 1 eq),diisopropylethylamine (104 mg, 0.80 mmol, 2 eq). The resulting solutionwas stirred overnight at room temperature and diluted withdichloromethane (150 ml) and washed with water (100 ml), dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum togive a residue, which was applied onto a silica gel column with 0.5%methanol in dichloromethane to afford crude product (50 mg), which waspurified by Flash-Prep-HPLC to afford1-[4-(naphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-onetrifluoroacetic acid salt as a yellow solid (39.4 mg, 15%). (ES, m/z):[M+H]⁺ 557; ¹H NMR (300 MHz, CD₃OD): δ 8.000 (d, J=9.0 Hz, 1H),7.70-7.80 (m, 3H), 7.30-7.45 (m, 4H), 6.97 (d, J=2.1 Hz, 1H), 6.75-6.79(m, 1H), 4.33 (s, 2H), 3.75-3.88 (m, 4H), 3.40-3.52 (m, 2H), 3.32-3.40(m, 4H), 2.08-2.22 (m, 4H), 1.42-1.58 (m, 2H), 1.27-1.42 (m, 2H).

Example 6 Preparation of Compound 17

Step 1. Formation of 1-(6-fluoronaphthalen-2-yl)piperazine

To a solution of 2-bromo-6-fluoronaphthalene (1 g, 4.44 mmol) in 30 mlof toluene was added sodium tert-butoxide (0.854 g, 8.89 mmol, 2.0 eq),piperazine (0.764 g, 8.87 mmol, 2.0 eq), BINAP (28 mg, 0.045 mmol, 1 mol%) and Pd₂(dba)₃.CHCl₃ (92 mg, 0.089 mmol, 2 mol %) at 70° C. in an oilbath under an inert atmosphere of nitrogen. The resulting solution wasstirred overnight and then concentrated under vacuum. The crude materialwas purified by silica gel chromatography using 10-20% methanol indichloromethane to elute. The product-containing fractions were combinedand concentrated under vacuum to afford1-(6-fluoronaphthalen-2-yl)piperazine as a light yellow solid (0.75 g,73%). (ES, m/z): [M+H]⁺ 231.1; ¹H NMR (300 MHz, CDCl₃): δ 7.67-7.73 (m,2H), 7.29-7.38 (m, 2H), 7.18-7.23 (m, 1H), 7.14 (d, J=1.8 Hz, 1H), 3.24(dd, J=3.6, 3.9 Hz, 4H), 3.12 (dd, J=3.6, 3.9 Hz, 4H).

Step 2. Formation of1-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoro-methyl)phenyl]amino]cycl-ohexyl)oxy]ethan-1-one(#17)

To a solution of2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)-oxy]aceticacid (173 mg, 0.48 mmol, 1 eq) in dichloromethane (50 ml) was added DIEA(61.8 mg, 0.48 mmol, 1 eq), HATU (182 mg, 0.48 mmol, 1 eq) and1-(6-fluoronaphthalen-2-yl)piperazine (110 mg, 0.48 mmol, 1 eq) at roomtemperature under an inert atmosphere of nitrogen. The resultingsolution was stirred overnight. The reaction was then quenched by theaddition of water (100 ml) and extracted with dichloromethane (3×50 ml)and the organic layers were combined and then dried over anhydroussodium sulfate. The solids were filtered off. The resulting mixture wasconcentrated under vacuum to give a residue, which was applied onto asilica gel column and eluted with 2% methanol in dichloromethane. Theproduct-containing fractions were combined and concentrated under vacuumto afford1-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneas a yellow solid (31.1 mg, 11%); (ES, m/z): [M−H]⁻ 573.2; ¹H NMR (300MHz, DMSO/D₂O): δ 8.05 (d, J=6.9 Hz, 1H), 7.77-7.82 (m, 2H), 7.53-7.56(dd, J=1.8, 7.5 Hz, 1H), 7.43-7.46 (dd, J=1.5, 6.9 Hz, 1H), 7.28-7.33(m, 1H), 7.25 (d, J=1.2 Hz, 1H), 7.06 (s, 1H), 6.83-6.86 (dd, J=1.8, 6.9Hz, 1H), 4.21 (s, 2H), 3.63 (broad s, 4H), 3.37-3.52 (m, 2H), 3.21-3.26(m, 4H), 1.94-2.05 (m, 4H), 1.34-1.39 (m, 2H), 1.23-1.29 (m, 2H).

Example 7 Preparation of Compound 088

Step 1. Formation of2-((1R,4R)-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)-1-(4-(quinolin-2-yl)piperazin-1-yl)ethanone(#88)

To a solution of 2-(piperazin-1-yl)quinoline (150 mg, 0.70 mmol) indichloromethane (30 ml) was added2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid(300 mg, 0.83 mmol, 1.2 eq), EDAC.HCl (201 mg, 1.05 mmol, 1.5 eq), HOBt(142.6 mg, 1.06 mmol, 1.5 eq) and triethylamine (213 mg, 2.10 mmol, 3eq). The resulting solution was stirred overnight at room temperature,quenched by the addition of water (50 ml), and then extracted withdichloromethane (3×50 ml). The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and then concentrated under vacuumto give a residue. The crude material was purified by Pre-TLC using 5%methanol in dichloromethane to elute. The product-containing fractionswere combined and then concentrated under vacuum to afford 229 mg (58%)of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-(quinolin-2-yl)piperazin-1-yl]ethan-1-oneas a yellow solid. (ES, m/z): [M+H]⁺ 558.40; ¹H NMR (300 MHz, CDCl₃): δ7.94-8.03 (m, 2H), 7.71 (s, 1H), 7.55-7.65 (m, 2H), 7.28-7.30 (t, J=5.4Hz, 1H), 6.99 (d, J=9.0 Hz, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.61-6.65 (m,1H), 4.51 (d, J=7.5 Hz, 1H), 4.27 (s, 2H), 3.74-3.96 (m, 8H), 3.34-3.51(m, 2H), 2.14-2.17 (m, 4H), 1.50-1.60 (m, 2H), 1.36-1.47 (m, 2H).

Example 8 Preparation of Compound 097

Step 1. Formation of cinnamoyl chloride

Cinnamic acid (25 g, 168.74 mmol) was treated with SOCl₂ (150 ml) for 2hours at 70° C. in a round-bottomed flask. The volatiles were distilledout under vacuum to afford cinnamoyl chloride as a yellow oil (25.2 g,crude), which was used in the next step without further purification.

Step 2. Formation of N-(4-fluorophenyl)cinnamamide

In a round-bottomed flask, a solution of the crude cinnamoyl chloride(25.2 g) in dichloromethane (50 ml) was added to a stirring mixture ofpyridine (14.4 g, 182 mmol) and 4-dimethylaminopyridine (1.44 g, 11.8mmol) in dichloromethane (100 ml) at 0° C. and stirred for 15 minutesbefore a solution of 4-fluoroaniline (13.2 g, 118.79 mmol) indichloromethane (50 ml) was added over 20 min. After being stirred for 3h at room temperature, the mixture was quenched with water (500 ml) andextracted with dichloromethane (3×150 ml). The organic layers werecombined, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum to give a residue. The crude material waspurified by silica gel chromatography using 1-5% ethyl acetate inpetroleum to elute. The product-containing fractions were combined toafford N-(4-fluorophenyl)cinnamamide as a light yellow solid (17.8 g,61%); (ES, m/z): [M+H]⁺ 242; ¹H NMR (300 MHz, CDCl₃): δ 10.28 (s, 1H),7.70-7.75 (m, 5H), 7.39-7.65 (m, 3H), 7.15 (t, J=9.0 Hz, 2H), 6.79 (d,J=15.6 Hz, 1H).

Step 3. Formation of 6-fluoro-1,2-dihydroquinolin-2-one

An intimate mixture of N-(4-fluorophenyl)cinnamamide (10 g, 42 mmol) andaluminum trichloride (16.4 g, 123 mmol, 3 eq) was heated rapidly tomelting and then heated at 100° C. for 3 h. After cooling to roomtemperature, ice-water was added and the resultant precipitate waswashed with water (300 ml) and then with 5% aqueous hydrochloric acid(3×100 ml) to afford 6-fluoro-1,2-dihydroquinolin-2-one as a brown solid(7.8 g, 88%) which was used without further purification; (ES, m/z):[M+H]⁺ 164; ¹H NMR (300 MHz, DMSO): δ 11.82 (broad s, 1H), 7.86 (d,J=9.4 Hz, 1H), 7.61 (d, J=8.7 Hz, 1H), 7.29-7.40 (m, 2H), 6.54 (d, J=9.4Hz, 1H).

Step 4. Formation of 2-chloro-6-fluoroquinoline

6-fluoro-1,2-dihydroquinolin-2-one (7.8 g, 47.8 mmol) was suspended inphosphorus oxychloride (72.2 g, 470.9 mmol) and stirred for 4 hours at100° C. in an oil bath. The reaction mixture was concentrated undervacuum to remove the excess phosphorus oxychloride and then ice-water(200 ml) was added. The precipitate that formed was washed with water(2×80 ml) and dried to give 2-chloro-6-fluoroquinoline as a off-whitesolid (6.8 g, 78%); (ES, m/z): [M+H]⁺ 182; ¹H NMR (300 MHz, DMSO): δ8.43 (d, J=8.4 Hz, 1H), 8.01 (dd, J=5.4 Hz, 9.3 Hz, 1H), 7.87 (dd, J=3.0Hz, 9.3 Hz, 1H), 7.72-7.78 (m, 1H), 7.45 (d, J=8.4 Hz, 1H).

Step 5. Formation of 6-fluoro-2-(piperazin-1-yl)quinoline

To a solution of 2-chloro-6-fluoroquinoline (6.8 g, 37.4 mmol) inN,N-dimethylformamide (200 ml) in a round-bottomed flask was addedpotassium carbonate (10.4 g, 75.2 mmol) and piperazine (19.2 g, 222.9mmol) at room temperature. After heating the contents to 130° C. for 5hours, the reaction mixture was concentrated under vacuum to a minimumvolume and then quenched with water (300 ml) and extracted withdichloromethane (3×200 ml). The combined organic layers were washed withbrine (100 ml), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The crude material was purified by silica gelchromatography using 1-2.5% methanol in dichloromethane to elute. Theproduct containing fractions were combined and concentrated to afford6-fluoro-2-(piperazin-1-yl)quinoline as a brown solid (4.5 g, 52%); (ES,m/z): [M+H]⁺ 232; ¹H NMR (300 MHz, CDCl₃): δ 7.86 (d, J=9.3 Hz, 1H),7.62-7.72 (m, 1H), 7.32-7.36 (m, 1H), 7.24-7.29 (m, 1H), 7.01 (d, J=9.3Hz, 1H), 3.73 (t, J=5.1 Hz, 4H), 3.05 (t, J=5.1 Hz, 4H).

Step 6. Formation of1-[4-(6-fluoroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one (#97)

To a solution of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl) oxy]aceticacid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl(79.1 mg, 0.41 mmol), HOBt (55.9 mg, 0.41 mmol), triethylamine (83.7 mg,0.83 mmol) and 6-fluoro-2-(piperazin-1-yl)quinoline (70.2 mg, 0.30 mmol)at room temperature. After stirred overnight, the reaction mixture wasthen diluted with dichloromethane (100 ml) and washed with water (2×100ml), dried over anhydrous magnesium sulfate, filtered, and concentratedunder vacuum to give a residue, which was purified by a silica gelcolumn with 2% methanol in dichloromethane to afford1-[4-(6-fluoroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneas a yellow solid (80 mg, 48%); (ES, m/z): [M+H]⁺ 576.20; ¹H NMR (400MHz, CDCl₃): δ 8.02 (d, J=8.8 Hz, 1H), 7.94-7.99 (m, 1H), 7.72-7.78 (m,1H), 7.31-7.37 (m, 2H), 7.02 (t, J=8.0 Hz, 1H), 6.87 (s, 1H), 6.64 (dd,J=2.4 Hz, 9.2 Hz, 1H), 4.48 (d, J=7.6 Hz, 1H), 4.28 (s, 2H), 3.75-3.81(m, 7H), 3.41-3.49 (m, 2H), 2.17-2.19 (m, 4H), 1.50-1.58 (m, 2H),1.28-1.36 (m, 3H).

Example 9 Preparation of Compound 90

Step 1. Formation of tert-butyl4-(6-chloroquinolin-2-yl)piperazine-1-carboxylate

To a solution of 2,6-dichloroquinoline (1.5 g, 7.6 mmol) in DMF (50 ml)was added tert-butyl piperazine-1-carboxylate (7.1 g, 38.1 mmol, 5 eq),and potassium carbonate (2.1 g, 15.1 mmol, 2 eq). The mixture wasstirred for 4 hours at 140° C. and then quenched by the addition ofwater (300 ml) and then extracted with ethyl acetate (3×100 ml). Theorganic layers were combined, washed with saturated aqueous sodiumchloride (3×300 ml), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to give a residue. The crude material waspurified by silica gel chromatography using 1-10% ethyl acetate inpetroleum ether to elute. The product-containing fractions were combinedand concentrated under vacuum to afford tert-butyl4-(6-chloroquinolin-2-yl)piperazine-1-carboxylate as a light yellowsolid (1.6 g, 61%). (ES, m/z): [M+H]⁺ 348; ¹H NMR (300 MHz, DMSO): δ8.03 (d, J=9.3 Hz, 1H), 7.81 (d, J=2.1 Hz, 1H), 7.50-7.58 (m, 2H), 7.29(d, J=9.3 Hz, 1H), 3.68-3.71 (t, J=5.1 Hz, 4H), 3.43-3.47 (t, J=4.5 Hz,4H), 1.43 (s, 9H).

Step 2. Formation ofN-(2-aminoethyl)-6-chloro-N-(2-chloroethyl)quinolin-2-amine

HCl (gas) was transferred into a solution of tert-butyl 4-(6-chloroquinolin-2-yl)piperazine-1-carboxylate (1.6 g, 4.6 mmol) in methanol (40ml) at room temperature with stirring for 1 hour and then concentratedunder vacuum to affordN-(2-aminoethyl)-6-chloro-N-(2-chloroethyl)quinolin-2-amine as a whitesolid (1.1 g, 84%). (ES, m/z): [M+H]⁺ 248

Step 3. Formation of1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one (#90)

To a solution of2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid(100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl (79.4mg, 0.41 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine(111.6 mg, 1.10 mmol, 4 eq), andN-(2-aminoethyl)-6-chloro-N-(2-chloroethyl)quinolin-2-amine (93.8 mg,0.33 mmol, 1.2 eq). The resulting solution was stirred overnight at roomtemperature and then quenched by the addition of water (50 ml),extracted with dichloromethane (3×30 ml). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to give a residue. The crude material waspurified by Pre-TLC using 4% methanol in dichloromethane to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneas a yellow solid (69.8 mg, 42%). (ES, m/z): [M+H]⁺ 592.35; ¹H NMR (300MHz, CDCl₃): δ 8.00 (d, J=9.0 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 7.61 (s,2H), 7.52 (s, 1H), 7.01 (d, J=9.0 Hz, 1H), 6.91 (s, 1H), 6.84 (d, J=2.4Hz, 1H), 6.61-6.65 (m, 1H), 4.45 (d, J=7.5 Hz, 1H), 4.26 (s, 2H),3.75-3.78 (m, 7H), 3.37-3.50 (m, 2H), 2.14 (d, J=10.5 Hz, 4H), 1.44-1.51(m, 2H), 1.24-1.35 (m, 2H).

Example 10 Preparation of Compound 89

Step 1. Formation of 3,3-diethoxypropanoic acid

To a solution of ethyl 3,3-diethoxypropanoate (20 g, 105 mmol) in water(80 ml) was added sodium hydroxide (5 g, 125 mmol, 1.2 eq). Theresulting solution was stirred for 1 hour at 110° C. in an oil bath andthen adjusted to pH 5 with aqueous hydrogen chloride (3N). The crudeproduct was then extracted with tetrahydrofuran (3×80 ml) and theorganic layers were combined, dried over anhydrous sodium sulfate, andfiltered before being concentrated under vacuum. The crude residue waspurified by silica gel chromatography using 3-50% ethyl acetate inpetroleum ether to elute. The product-containing fractions were combinedand concentrated under vacuum to afford 3,3-diethoxypropanoic acid aslight yellow oil (12 g, 70%); ¹H NMR (300 MHz, DMSO): δ 4.80-4.82 (t,J=5.7 Hz, 1H), 3.41-3.61 (m, 4H), 2.49 (d, J=5.7 Hz, 2H), 1.06-1.24 (m,6H).

Step 2. Formation of (2E)-3-ethoxyprop-2-enoyl chloride

3,3-diethoxypropanoic acid (5 g, 30.83 mmol) was added to thionylchloride (20 ml) with stirring at 0° C. and then heated to 80° C. for 1hour (oil bath). The resulting mixture was then concentrated undervacuum to afford (2E)-3-ethoxyprop-2-enoyl chloride as dark red oil (4g, crude).

Step 3. Formation of (2E)-3-ethoxy-N-(4-methylphenyl)prop-2-enamide

To a solution of 4-(trifluoromethyl)aniline (2.56 g, 15.9 mmol) indichloromethane (40 ml) was added pyridine (3.77 g, 47.7 mmol). Thesolution was cooled to 0° C. before a solution of 3,3-diethoxypropanoylchloride (4 g, crude) in dichloromethane (10 ml) was added dropwise withstirring. The resulting solution was stirred for 4 hours at 20° C. andthen washed with water (200 ml). The resulting mixture was extractedwith dichloromethane (3×80 ml) and the organic layers were combined andconcentrated under vacuum. The crude residue was purified by Pre-TLCwith 1-20% ethyl acetate in petroleum ether to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford (2E)-3-ethoxy-N-(4-trifluoromethylphenyl)prop-2-enamide as ayellow solid (4.0 g). (ES, m/z): [M+H]⁺ 260; ¹H NMR (300 MHz, DMSO): δ10.10 (s, 1H), 7.83 (d, J=8.4 Hz, 2H), 7.72 (s, 1H), 7.60 (d, J=8.7 Hz,1H), 7.50-7.56 (m, 1H), 5.52 (d, J=12.4 Hz, 1H), 3.90-4.01 (m, 2H),1.15-1.30 (m, 3H).

Step 4. Formation of 6-(trifluoromethyl)-1,2-dihydroquinolin-2-one

(2E)-3-ethoxy-N-(4-trifluoromethylphenyl)prop-2-enamide (3.44 g, 16.8mmol) was added in several batches to sulfuric acid (20 ml) at 0° C. andthen stirred for 2 hours at 0° C. The resulting mixture was quenchedwith ice-water (100 ml). The product was precipitated from water andcollected by filtration to afford6-(trifluoromethyl)-1,2-dihydroquinolin-2-one as a yellow solid (2.0 g,56%). (ES, m/z): [M+H]⁺ 214. ¹H NMR (300 MHz, DMSO): δ 8.14 (s, 1H),8.03 (d, J=9.6 Hz, 1H), 7.80-7.83 (m, 1H), 7.45 (d, J=8.4 Hz, 1H),6.61-6.65 (t, J=9.6 Hz, 1H).

Step 5. Formation of 2-chloro-6-(trifluoromethyl)quinoline

6-(trifluoromethyl)-1,2-dihydroquinolin-2-one (1.0 g, 4.7 mmol) wasdissolved in POCl₃ (15 ml) and stirred for 2 h at 110° C. (oil bath).The resulting mixture was dissolved in ice-water (100 ml) and adjustedpH to 8 with aqueous Na₂CO₃ solution (3N). The crude product was thenextracted with dichloromethane (3×80 ml) and the organic layers werecombined, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum to afford2-chloro-6-(trifluoromethyl)quinoline as a dark red solid (944 mg, 87%).(ES, m/z): [M+H]⁺ 232. ¹H NMR (300 MHz, DMSO): δ 8.59-8.66 (m, 2H),8.01-8.17 (m, 2H), 7.75 (d, J=8.7 Hz, 1H).

Step 6. Formation of 2-(piperazin-1-yl)-6-(trifluoromethyl)quinoline

To a solution of 2-methyl-6-(trifluoromethyl)quinoline (1.5 g, 7.10mmol) in 1N,N-dimethylformamide (50 ml) was added piperazine (2.8 g,32.51 mmol) and potassium carbonate (1.8 g, 12.93 mmol). The resultingsolution was stirred for 3 hours at 140° C. and then quenched by theaddition of water (200 ml). The crude product was extracted with ethylacetate (3×100 ml) and the organic layers were combined. The resultingmixture was washed with saturated aqueous sodium chloride (3×100 ml),dried over anhydrous sodium sulfate, filtered, and then concentratedunder vacuum. The crude residue was purified by silica gelchromatography using 1-5% methanol in dichloromethane to elute. Theproduct-containing fractions were combined and concentrated to afford2-(piperazin-1-yl)-6-(trifluoromethyl)quinoline as a brown solid (1.3 g,65%). (ES, m/z): [M+H]⁺ 282; ¹H NMR (300 MHz, DMSO): δ 8.17-8.23 (t,J=9.3, 2H), 7.66-7.77 (m, 2H), 7.63 (d, J=9.3 Hz, 1H), 3.78-3.81 (t,J=4.5 Hz, 4H), 2.92-2.96 (t, J=4.5 Hz, 4H).

Step 7. Formation of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-[6-trifluoro-methyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one(#89)

To a solution of2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid(100 mg, 0.28 mmol) in dichloromethane (20 ml) was added2-(piperazin-1-yl)-6-(trifluoromethyl)quinoline (93.1 mg, 0.33 mmol, 1.2eq), EDAC.HCl (79 mg, 0.41 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5eq), Et₃N (84 mg, 0.83 mmol, 3 eq). The resulting solution was stirredovernight at room temperature and then quenched by the addition of water(50 ml), extracted with of dichloromethane (3×30 ml) and the organiclayers were combined and dried over anhydrous sodium sulfate. Theorganic solution was filtered and then concentrated under vacuum. Thecrude material was purified by Pre-TLC using 4% methanol indichloromethane to elute. Concentration of the product-containingfractions afforded2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-oneas a yellow solid (77 mg, 45%).

(ES, m/z): [M+H]⁺ 626.40. ¹H NMR (300 MHz, CD₃OD): δ 8.13 (d, J=9.0 Hz,1H), 8.02-8.05 (t, J=4.5 Hz, 2H), 7.42-7.79 (m, 2H), 7.29 (d, J=9.3 Hz,1H), 6.99 (d, J=2.4 Hz, 1H), 6.78-6.81 (dd, J=2.4, 9.2 Hz, 1H), 4.34 (s,2H), 3.88-3.94 (m, 4H), 3.72-3.78 (m, 4H), 3.45-3.50 (m, 2H), 2.10-2.20(m, 4H), 1.34-1.54 (m, 4H).

Example 11 Preparation of Compound 98

Step 1. Formation of 4-methyl-2-(piperazin-1-yl)quinoline

To a solution of 2-chloro-4-methylquinoline (2 g, 11 mmol) inN,N-dimethylformamide (40 ml) was added piperazine (4.86 g, 56.4 mmol, 5eq) and potassium carbonate (2.34 g, 16.8 mmol, 1.5 eq). The mixture wasstirred overnight at 140° C., quenched by the addition of water (200ml), and extracted with ethyl acetate (3×100 ml). The organic layerswere combined and washed with saturated aqueous sodium chloride (200ml). The ethyl acetate solution was dried over anhydrous sodium sulfate,filtered, and concentrated under vacuum. The crude material was purifiedby silica gel chromatography using 1-10% methanol in dichloromethane toelute. The product-containing fractions were combined and concentratedto afford 4-methyl-2-(piperazin-1-yl)quinoline as colorless oil (2.2 g,86%); (ES, m/z) [M+H]⁺ 228; ¹H NMR (300 MHz, CDCl₃): δ 7.70-7.78 (m,2H), 7.50-7.55 (t, J=7.5 Hz, 1H), 7.22-7.27 (t, J=6.9 Hz, 1H), 6.83 (s,2H), 3.70-3.73 (t, J=4.8 Hz, 1H), 3.00-3.03 (t, J=5.1 Hz, 1H), 2.59 (s,3H).

Step 2. Formation of1-[4-(4-methylquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one (#98)

To a solution of 4-methyl-2-(piperazin-1-yl)quinoline (100 mg, 0.44mmol) in dichloromethane (20 ml) was added EDAC.HCl (126 mg, 0.66 mmol,1.5 eq), HOBt (88.8 mg, 0.66 mmol, 1.5 eq), triethylamine (133 mg, 1.31mmol, 3 eq) and2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid(190 mg, 0.52 mmol, 1.2 eq). The resulting solution was stirredovernight at room temperature and then quenched by the addition of water(50 ml) and extracted with dichloromethane (3×30 ml). The organic layerswere combined, dried over anhydrous sodium sulfate, filtered, and thenconcentrated under vacuum to give a residue. The crude material waspurified by Pre-TLC with 50% ethyl acetate in dichloromethane to afford1-[4-(4-methylquinolin-2-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoro-methyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneas a yellow solid (117 mg, 47%); (ES, m/z) [M+H]⁺ 572.20; ¹H NMR (300MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.74 (s,1H), 7.54-7.62 (m, 1H), 7.32-7.38 (m, 1H), 6.87 (s, 2H), 6.63-6.67 (m,1H), 4.48 (d, J=7.5 Hz, 1H), 4.28 (s, 2H), 3.75-3.85 (m, 7H), 3.39-3.52(m, 2H), 2.65 (s, 3H), 2.16 (d, J=9.9 Hz, 1H), 1.46-1.53 (m, 2H),1.25-1.36 (m, 2H).

Example 12 Preparation of Compound 24

Step 1. Formation of allyloxybenzene

To a round-bottomed flask containing a solution of phenol (30 g, 319mmol) in acetonitrile (150 ml) at room temperature was added potassiumcarbonate (66 g, 478 mmol) and allyl bromide (49.8 g, 412 mmol). Themixture was heated to 50° C. and stirred for 3.5 hours. The solids werefiltered out and the filtrate was concentrated to a minimum volume. Thecrude material was diluted with water (200 ml) and extracted with ethylacetate (3×100 ml). The combined organic layers were washed with brine(2×100 ml), dried over anhydrous magnesium sulfate, filtered, andconcentrated to afford crude allyloxybenzene as brown oil (35 g); ¹H NMR(300 MHz, CDCl₃): δ 7.20-7.30 (m, 2H), 6.89-6.96 (m, 3H), 5.99-6.12 (m,1H), 5.41 (d, J=17.1 Hz, 1H), 5.28 (d, J=10.5 Hz, 1H), 4.52 (d, J=5.1Hz, 2H).

Step 2. Formation of 2-allylphenol

A solution of allyloxybenzene (34 g, crude) in dichloromethane (200 ml)was treated with a 1N solution of BCl₃ (279 ml, 279 mmol) indichloromethane at between −30 to −20° C. under an inert atmosphere ofnitrogen. After 30 minutes of stirring, the reaction mixture was thenquenched with ice-water (200 ml) and the organic layer was separated.The aqueous layer was extracted with ethyl acetate (2×100 ml). Thecombined organic layers were washed with saturated aqueous sodiumbicarbonate (200 ml), dried over anhydrous magnesium sulfate, filtered,and concentrated under vacuum. The crude material was purified by silicagel chromatography with 0.5-2.5% ethyl acetate in petroleum ether toelute. The product-containing fractions were combined and concentratedunder vacuum to afford 2-(prop-2-en-1-yl)phenol as light yellow oil (23g, 66%); ¹H NMR (300 MHz, CDCl₃): δ 7.09-7.15 (m, 2H), 6.85-6.95 (m,1H), 6.80 (d, J=7.8 Hz, 1H), 5.93-6.08 (m, 1H), 5.12-5.18 (m, 1H),5.02-5.09 (m, 1H), 3.41 (d, J=6.3 Hz, 2H).

Step 3. Formation of 2-(iodomethyl)-2,3-dihydro-1-benzofuran

To a solution of 2-allylphenol (10 g, 75 mmol) in dichloromethane (150ml) was added SnCl₄ (29.7 g, 37.3 mmol, 0.5 eq) and iodine (19 g, 75mmol, 1 eq) at room temperature. After stirring for 5.5 hours, thereaction mixture was diluted with additional dichloromethane (200 ml)and then quenched with water (200 ml). The organic layer was separatedand the aqueous layer was adjusted pH to ˜8 with sodium bicarbonate andthen extracted with dichloromethane (3×150 ml). The organic layers werecombined, washed with 5% aqueous Na₂S₂O₄ (200 ml), dried over anhydrousmagnesium sulfate, filtered, and then concentrated under vacuum. Thecrude material was purified by silica gel chromatography using with0.5-1% ethyl acetate in petroleum ether to elute. The product-containingfractions were combined and concentrated to afford2-(iodomethyl)-2,3-dihydro-1-benzofuran as brown oil (7 g, 36%); ¹H NMR(300 MHz, CDCl₃): δ 7.09-7.17 (m, 2H), 6.74-6.89 (m, 2H), 4.84-4.93 (m,1H), 3.30-3.47 (m, 3H), 3.00-3.08 (m, 1H).

Step 4. Formation of 1-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazine

To a solution of 2-(iodomethyl)-2,3-dihydro-1-benzofuran (5.3 g, 20.4mmol) in acetonitrile (70 ml) was added potassium carbonate (5.6 g, 40.5mmol, 2 eq) and piperazine (8.8 g, 102.2 mmol, 5 eq). The resultingmixture was heated at reflux for 2 hours. The solids were then filteredoff and the filtrate was concentrated under vacuum. The crude materialwas purified by silica gel chromatography using 0.5-2.5% methanol indichloromethane to elute. The product-containing fractions were combinedand concentrated under vacuum to afford1-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazine as brown oil (2.4 g,54%); (ES, m/z): [M+H]⁺ 219; ¹H NMR (300 MHz, CDCl₃): δ 7.07-7.17 (m,2H), 6.78-6.85 (m, 2H), 4.92-5.01 (m, 1H), 3.22 (dd, J=9.0 Hz, 15.6 Hz,1H), 2.91-2.99 (m, 4H), 2.71-2.82 (m, 1H), 2.53-2.71 (m, 6H).

Step 5. Formation of1-[4-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one(#24)

To a solution of2-[(4-[4-nitro-3-(trifluoromethyl)phenyl]aminocyclohexyl)oxy]acetic acid(900 mg, 2.48 mmol) in dichloromethane (50 ml) was added EDAC.HCl (661mg, 3.45 mmol), HOBt (464 mg, 3.43 mmol), triethylamine (463 mg, 4.58mmol) and 1-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazine (500 mg,2.29 mmol) in dichloromethane (1 ml) with stirring for overnight at roomtemperature. Then the mixture was diluted with dichloromethane (300 ml)and washed with water (100 ml). The organic layer was dried overanhydrous magnesium sulfate, filtered, and concentrated under vacuum togive a residue, which was purified by a silica gel column, eluted with0.5%-3% methanol in dichloromethane to afford1-[4-(2,3-dihydro-1-benzofuran-2-ylmethyl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneas a yellow solid (462.4 mg, 36%); (ES, m/z): [M+H]⁺ 563.00; ¹H NMR (300MHz, CDCl₃): δ 8.00 (d, J=8.7 Hz, 1H), 7.09-7.18 (m, 2H), 6.77-6.88 (m,3H), 6.61 (dd, J=2.1 Hz, 8.7 Hz, 1H), 5.03 (broad s, 1H), 4.45 (d, J=6.9Hz, 1H), 4.20 (s, 2H), 3.67-3.78 (m, 3H), 3.40-3.49 (m, 3H), 2.66-2.99(m. 6H), 2.13-2.23 (m, 4H), 1.41-1.63 (m, 3H), 1.21-1.34 (m, 3H).

Example 13 Preparation of Compound 77

Step 1. Formation of 1-allyloxy-4-fluoro-benzene

Into a 1 L round-bottomed flask containing 500 ml of acetonitrile wasadded 4-fluorophenol (30.0 g, 267.6 mmol), 3-bromoprop-1-ene (41.7 g,344.7 mmol, 1.3 eq), and potassium carbonate (55 g, 398 mmol, 1.5 eq).The mixture was stirred for 3.5 hours at 60° C. (oil bath). The solidswere filtered off and the filtrate was concentrated under vacuum leaving25.0 grams of the crude product as a yellow oil; 61%.

Step 2. Formation of 2-allyl-4-fluoro-phenol

In a 250 ml round-bottomed flask, 1-allyloxy-4-fluoro-benzene (23.0 g,151 mmol) was heated at 260° C. for 5 hours. The crude product waspurified by silica gel chromatography using petroleum ether/ethylacetate to elute. The product containing fractions were concentratedunder vacuum to provide 18.0 grams (78%) of a yellow oil.

Step 3. Formation of 5-fluoro-2-iodomethyl-2,3-dihydro-benzofuran

To a solution of 4-fluoro-2-(prop-2-en-1-yl)phenol (5 g, 32.9 mmol) indichloromethane (125 mL) was added SnCl₄ (4.28 g, 16.5 mmol) and iodine(8.36 g, 32.9 mmol) at room temperature. After an additional 18 hours,the reaction was quenched with water (150 ml) and the pH value wasadjusted to ˜8 with aqueous sodium hydroxide solution (2N). The organiclayer was separated and the aqueous layer was extracted withdichloromethane (2×100 mL). The combined organic layer was washed withNa₂S₂O₄ (3×100 mL, 5%) to remove iodine and dried over anhydrousmagnesium sulfate. The solution was filtered and concentrated undervacuum. The crude residue was purified by silica gel chromatographyusing 0.5-1% ethyl acetate in petroleum ether to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford 5-fluoro-2-(iodomethyl)-2,3-dihydro-1-benzofuran as a yellowoil (5 g, 54%); ¹H NMR (300 MHz, DMSO): δ 7.03-7.08 (dd, J=5.7 Hz, 8.4Hz, 1H), 6.93-6.86 (dt, J=2.7 Hz, 8.7 Hz, 1H), 6.76-6.70 (m, 1H),4.88-4.79 (m, 1H), 3.49-3.60 (m, 2H), 3.41-3.32 (dd, J=7.2 Hz, 16.5 Hz,1H), 2.96-2.88 (dd, J=7.2 Hz, 16.5 Hz, 1H).

Step 4. Formation of1-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazine

Into a 100 ml round-bottomed flask containing 40 ml of acetonitrile wasadded 5-fluoro-2-iodomethyl-2,3-dihydro-benzofuran (5.7 g, 20.5 mmol),piperazine (6.6 g, 76.6 mmol, 4 eq), and potassium carbonate (4.2 g,30.4 mmol, 1.5 eq). The mixture was stirred at room temperature for 4hours. The reaction contents were diluted with water and then extractedwith 3×200 ml of ethyl acetate. The organic layers were combined, driedover sodium sulfate, filtered, and then concentrated under vacuum. Thecrude material was then purified via silica gel chromatography usingmethanol/dichloromethane to elute. The product containing fractions werethen concentrated under vacuum to provide 2.2 g (45%) of the substitutedpiperazine as a dark red oil.

Step 5. Formation of2-chloro-1-[4-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazin-1-yl]-ethanone(#77)

Into a 50 ml round-bottomed flask containing 20 ml of dichloromethanewas added 1-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazine (100mg, 0.42 mmol),2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]aceticacid (230 mg, 0.63 mmol, 1.5 eq), EDAC.HCl (122 mg, 0.64 mmol, 1.5 eq),HOBt (86 mg, 0.64 mmol, 1.5 eq) and triethylamine (128 mg, 1.26 mmol,3.0 eq). The solution was stirred at room temperature for 16 hours. Thecrude contents were diluted with water and then extracted with 3×50 mlof ethyl acetate. The organic fractions were combined, dried overmagnesium sulfate, filtered, and then concentrated under vacuum. Thecrude material was then chromatographed on silica gel usingmethanol/dichloromethane to elute. The product-containing fractions werethen combined and concentrated to provide 150 mg of the amide as a lightyellow solid (57%). (ES, m/z): [M+H]⁺ 581.3; ¹H NMR (300 MHz, CDCl₃): δ8.02 (d, J=9 Hz, 1H), 6.75-6.91 (m, 3H), 6.60-6.71 (m, 2H), 5.00 (broads, 1H), 4.48 (d, J=7.5 Hz, 1H), 3.66 (s, 2H), 3.48-3.80 (broad m, 4H),3.22-3.50 (broad m, 3H), 2.95 (m, 1H), 2.75-2.90 (m, 1H), 2.50-2.75(broad m, 4H), 2.16 (d, J=8.7 Hz, 4H), 1.38-1.58 (dd, J=10.5, 22.5 Hz,2H), 1.22-1.34 (dd, J=˜10.9, 22.5 Hz, 2H).

Example 14 Preparation of Compound 76

Step 1. Formation of 1-chloro-4-(prop-2-en-1-yloxy)benzene

To a solution of 4-chlorophenol (30 g, 233 mmol) in acetonitrile (100ml) was added potassium carbonate (48.1 g, 349 mmol, 1.5 eq) and allylbromide (36.28 g, 299.9 mmol, 1.3 eq) dropwise with stirring for 5 hoursat 50° C. in an oil bath. The solids were filtered out and the liquidwas concentrated under vacuum to afford1-chloro-4-(prop-2-en-1-yloxy)benzene as yellow oil (34 g, 86%); ¹H NMR(300 MHz, CDCl₃): δ 7.20-7.25 (m, 2H), 6.81-6.86 (m, 2H), 5.96-6.09 (m,1H), 5.27-5.44 (m, 2H), 4.49-4.51 (m, 2H).

Step 2. Formation of 4-chloro-2-(prop-2-en-1-yl)phenol

1-chloro-4-(prop-2-en-1-yloxy)benzene (34 g, 202 mmol) was stirred for 7hours at 260° C. The reaction mixture was purified via silica gelchromatography using 3% ethyl acetate in petroleum ether to elute. Theproduct-containing fractions were combined and concentrated to afford4-chloro-2-(prop-2-en-1-yl)phenol as light brown oil (17 g, crude); ¹HNMR (300 MHz, CDCl₃): δ 7.03-7.09 (m, 2H), 6.75 (d, J=3.0 Hz, 1H),5.92-6.05 (m, 1H), 5.13-5.20 (m, 2H), 3.37 (d, J=6.3 Hz, 2H).

Step 3. Formation of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol

To a solution of 4-chloro-2-(prop-2-en-1-yl)phenol (17 g, crude,nominally 101 mmol) in chloroform (100 ml) was added mCPBA (17.4 g, 101mmol, 1 eq) with stirring for 1 hour at 50° C. in an oil bath. Then thereaction mixture was concentrated under vacuum and re-dissolved in MeOH(100 ml). Potassium carbonate (27.6 g, 200 mmol, 2 eq) was added and themixture was stirred for 5 hours at 50° C. The solids were filtered offand the filtrate was concentrated under vacuum. The crude material waspurified by silica gel chromatography using 3% ethyl acetate inpetroleum ether to elute. The product-containing fractions were combinedand concentrated under vacuum to afford(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow oil (6.15 g);¹H NMR (300 MHz, CDCl₃): δ 7.00-7.18 (m, 2H), 6.80 (d, J=8.7 Hz, 1H),4.88-4.97 (m, 1H), 3.85-3.90 (m, 1H), 3.70-3.79 (m, 1H), 3.19-3.27 (dd,J=9.3 Hz, 15.9 Hz, 1H), 2.98-3.05 (dd, J=7.5 Hz, 15.9 Hz, 1H), 2.10(broad s, 1H).

Step 4. Formation of 5-chloro-2-(chloromethyl)-2,3-dihydro-1-benzofuran

To a solution of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol (3 g,16 mmol) in benzene (50 ml) was added pyridine (1.55 g, 19.6 mmol, 1.2eq) and thionyl chloride (2.72 g, 23.0 mmol) dropwise with stirring at0° C. for 7 hours at 80° C. in an oil bath. The reaction mixture wasadjusted to ˜pH 8 with aqueous sodium bicarbonate and then extractedwith ethyl acetate (3×50 mL). The organic layers were combined, driedover anhydrous magnesium sulfate, filtered, and concentrated undervacuum. The crude material was purified by silica gel chromatographyusing 3% ethyl acetate in petroleum ether to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford 5-chloro-2-(chloromethyl)-2,3-dihydro-1-benzofuran as anoff-white solid (1.5 g, 46%); ¹H NMR (300 MHz, CDCl₃): δ 7.06-7.14 (m,2H), 6.70 (d, J=8.4 Hz, 1H), 4.99-5.10 (m, 1H), 3.64-3.76 (m, 2H),3.32-3.40 (dd, J=9.3 Hz, 16.2 Hz, 1H), 3.09-3.17 (dd, J=6.6 Hz, 16.2 Hz.1H).

Step 5. Formation of1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine

To 5-chloro-2-(chloromethyl)-2,3-dihydro-1-benzofuran (1.6 g, 7.9 mmol)was added piperazine (2.72 g, 31.6 mmol, 4 eq) with stirring for 15hours at 135° C. in an oil bath. The crude material was purified bysilica gel chromatography using 3% dichloromethane in methanol to elute.The product-containing fractions were combined and concentrated undervacuum to afford1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine as a lightyellow solid (1.3 g, 65%); (ES, m/z): [M+H]⁺ 253; ¹H NMR (300 MHz,CDCl₃): δ 7.03-7.11 (m, 2H), 6.68 (d, J=8.4 Hz, 1H), 4.93-5.03 (m, 1H),3.20-3.29 (m, 1H), 2.88-2.99 (m, 6H), 2.72-2.79 (m, 1H), 2.49-2.63 (m,5H).

Step 6. Formation of2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one

To a solution of1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (1.3 g, 5.1mmol) in dichloromethane (50 ml) was added triethylamine (782 mg, 7.73mmol, 1.5 eq) and 2-chloroacetyl chloride (758 mg, 6.71 mmol, 1.3 eq)dropwise with stirring at 0° C. for 1 hour at room temperature. Thereaction mixture was quenched by the addition of water (80 ml) andextracted with dichloromethane (3×50 ml). The organic layers werecombined, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum. The crude material was purified by silica gelchromatography using 3% ethyl acetate in petroleum ether to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-oneas yellow oil (1.0 g, 59%); (ES, m/z): [M+H]⁺ 329; ¹H NMR (300 MHz,CDCl₃): δ 7.04-7.12 (m, 2H), 6.69 (d, J=8.4 Hz, 1H), 4.95-5.08 (m, 1H),4.11 (s, 2H), 3.56-3.73 (m, 5H), 3.23-3.32 (dd, J=9.3 Hz, 15.9 Hz, 1H),2.91-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (dd, J=7.8 Hz, 13.5 Hz,1H), 2.48-2.75 (m, 4H).

Step 7. Formation of1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one(#76)

To a solution of4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexan-1-ol (40 mg, 0.13mmol) in tetrahydrofuran (1 ml) and N,N-dimethylformamide (0.3 ml) wasadded sodium hydride (26 mg, 1.08 mmol, 8 eq) with stirring for 30minutes at 0° C. Then2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-one(90 mg, 0.27 mmol, 2 eq) in tetrahydrofuran (0.5 ml) was added withstirring for 5 hours at room temperature. The reaction mixture wasquenched by water (20 ml) and extracted with ethyl acetate (3×30 ml).The organic layers were combined and dried over anhydrous magnesiumsulfate, filtered, and concentrated under vacuum. The crude material waspurified by Pre-TLC using 50% ethyl acetate in petroleum ether to elute.The product-containing fractions were combined and concentrated undervacuum to afford1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneas a yellow solid (29.8 mg, 38%); (ES, m/z): [M+H]⁺ 597.35; ¹H NMR (300MHz, CDCl₃): δ 8.02 (d, J=7.2 Hz, 1H), 7.04-7.12 (m, 2H), 6.84 (d, J=2.4Hz, 1H), 6.61-6.71 (m, 2H), 5.01 (broad s, 1H), 4.46 (d, J=7.8 Hz, 1H),4.19 (s, 2H), 3.60-3.73 (m, 3H), 3.40-3.47 (m, 2H), 3.23-3.32 (dd, J=9.3Hz, 15.9 Hz, 1H), 2.92-2.99 (dd, J=7.8 Hz, 15.9 Hz, 1H), 2.77-2.84 (m,1H), 2.62-2.77 (m, 4H), 2.12-2.16 (m, 4H), 1.41-1.52 (m, 3H), 1.22-1.30(m, 3H).

Example 15 Preparation of Compound 78

Step 1. Formation of 1-(prop-2-en-1-yloxy)-4-(trifluoromethyl)benzene

To a solution of 4-(trifluoromethyl)phenol (50 g, 308 mmol) in CH₃CN(600 ml) was added potassium carbonate (64 g, 463 mmol, 1.5 eq) andallyl bromide (48 g, 397 mmol, 1.3 eq) with stirring for overnight at50° C. in an oil bath. The solids were filtered off and the filtrate wasconcentrated to a minimum volume, which was diluted by water (200 ml)and extracted with ethyl acetate (3×100 ml). The combined organic layerswere washed with brine (2×200 ml), dried over anhydrous magnesiumsulfate, filtered, and then concentrated under vacuum to afford1-(prop-2-en-1-yloxy)-4-(trifluoromethyl)benzene as yellow oil (35 g,56%); ¹H NMR (300 MHz, CDCl₃): δ 7.52 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7Hz, 2H), 5.98-6.11 (m, 1H), 5.30-5.46 (m, 2H), 4.57-4.58 (m, 2H).

Step 2. Formation of 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol

A solution of 1-(prop-2-en-1-yloxy)-4-(trifluoromethyl)benzene (30 g,148 mmol) in dichloromethane (250 ml) was treated with 1N solution ofBCl₃ (163 ml, 163 mmol, 1.1 eq) in dichloromethane for 2.5 hours at −20°C. under an inert atmosphere of nitrogen. The reaction mixture was thenquenched with ice-water (200 ml) and the organic layer was separatedout. The aqueous layer was extracted further with dichloromethane (3×200ml) and the combined organic layer was washed with saturated aqueoussodium bicarbonate (200 ml) and then dried over anhydrous magnesiumsulfate. The solution was filtered and then concentrated under vacuum toafford 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol as colorless oil (25g, 83%); ¹H NMR (300 MHz, CDCl₃): δ 7.38 (d, J=7.5 Hz, 2H), 6.86 (t,J=8.7 Hz, 1H), 5.94-6.07 (m, 1H), 5.60 (s, 1H), 5.15-5.22 (m, 2H), 3.43(d, J=6.6 Hz, 2H).

Step 3. Formation of2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran

To a solution of 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol (4 g, 20mmol) in dichloromethane (50 ml) was added SnCl₄ (2.6 g, 10.0 mmol, 0.5eq) dropwise and iodine (5.03 g, 19.8 mmol, 1 eq) with stirring for 6hours at room temperature. The reaction mixture was diluted withdichloromethane (200 ml) and quenched by the addition of water (100 ml).The organic layer was separated and the pH value of the aqueous layerwas adjusted to ˜8 with aqueous sodium bicarbonate. The aqueous layerwas extracted further with dichloromethane (3×100 ml). The organiclayers were combined, washed with aqueous Na₂S₂O₄ (5%, 100 ml) to removeremaining iodine, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum. The crude material was purified by silica gelchromatography using 1% ethyl acetate in petroleum ether to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford 2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran ascolorless oil (2.8 g, 43%); ¹H NMR (300 MHz, CDCl₃): δ 7.39 (d, J=5.7Hz, 2H), 6.83 (d, J=8.7 Hz, 1H), 4.91-5.00 (m, 1H), 3.34-3.48 (m, 3H),3.05-3.12 (m, 1H).

Step 4. Formation of1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine

To a solution of2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran (2.8 g, 8.5mmol) in CH₃CN (40 ml) was added potassium carbonate (2.36 g, 17.1 mmol,2 eq) and piperazine (2.94 g, 34.1 mmol, 4 eq) at room temperature. Themixture was heated at reflux for 3 hours, the solids were filtered off,and the filtrate was concentrated under vacuum. The crude material waspurified by silica gel chromatography using 1-2.5% methanol indichloromethane to elute. The product-containing fractions were combinedand concentrated under vacuum to afford1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazineas light yellow oil (1.25 g, 51%); (ES, m/z): [M+H]⁺ 287; ¹H NMR (300MHz, CDCl₃): δ 7.37 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.00-5.10(m, 1H), 3.26-3.35 (m, 1H), 2.96-3.04 (m, 1H), 2.88-2.95 (m, 4H),2.78-2.80 (m, 1H), 2.54-2.69 (m, 4H).

Step 5. Formation of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one(#78)

To a solution of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]aceticacid (100 mg, 0.28 mmol) in dichloromethane (30 ml) was added EDAC.HCl(79.6 mg, 0.42 mmol, 1.5 eq), HOBt (55.9 mg, 0.41 mmol, 1.5 eq),triethylamine (55.9 mg, 0.55 mmol, 1.5 eq) and1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine(86.9 mg, 0.30 mmol, 1.1 eq). The solution was stirred at roomtemperature overnight. The reaction mixture was diluted with water (50ml) and extracted with ethyl acetate (3×30 ml). The organic layers werecombined, dried over anhydrous magnesium sulfate, filtered, andconcentrated under vacuum. The crude material was purified by silica gelchromatography using 25% ethyl acetate in dichloromethane to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-oneas a yellow solid (69.9 mg, 40%); (ES, m/z): [M+H]⁺ 631.20; ¹H NMR (300MHz, CDCl₃): δ 8.01 (d, J=9.0 Hz, 1H), 7.44 (m, 2H), 6.84 (m, 2H), 6.62(dd, J=2.7 Hz, 9.0 Hz, 1H), 5.10 (broad s, 1H), 4.47 (d, J=8.1 Hz, 1H),4.22 (s, 2H), 3.61-3.82 (m, 3H), 3.36-3.48 (m, 3H), 3.01-3.07 (dd, J=7.8Hz, 16.2 Hz, 1H), 2.80-2.95 (m, 1H), 2.54-2.74 (m, 4H), 2.12-2.18 (m,4H), 1.43-1.59 (m, 3H), 1.24-1.35 (m, 3H).

Example 16 Preparation of Compound 83

Step 1. Formation of 1-allyloxy-4-fluoro-benzene

Into a 1 L round-bottomed flask containing 500 ml of acetonitrile wasadded 4-fluorophenol (30.0 g, 267.6 mmol), 3-bromoprop-1-ene (41.7 g,344.7 mmol, 1.3 eq), and potassium carbonate (55 g, 398 mmol, 1.5 eq).The mixture was stirred for 3.5 hours at 60° C. (oil bath). The solidswere filtered off and the filtrate was concentrated under vacuum leaving25.0 grams of the crude product as a yellow oil; 61%.

Step 2. Formation of 2-allyl-4-fluoro-phenol

In a 250 ml round-bottomed flask, 1-fluoro-4-(prop-2-en-1-uloxy)benzene(23.0 g, 151 mmol) was heated at 260° C. for 5 hours. The crude productwas purified by silica gel chromatography using petroleum ether/ethylacetate to elute. The product containing fractions were concentratedunder vacuum to provide 18.0 grams (78%) of a yellow oil.

Step 3. Formation of 5-fluoro-2-iodomethyl-2,3-dihydro-benzofuran

To a solution of 4-fluoro-2-(prop-2-en-1-yl)phenol (5 g, 32.9 mmol) indichloromethane (125 mL) was added SnCl₄ (4.28 g, 16.5 mmol) and iodine(8.36 g, 32.9 mmol) at room temperature. After an additional 18 hours,the reaction was quenched with water (150 ml) and the pH value wasadjusted to 8 with aqueous NaOH solution (2N). The organic layer wasseparated and the aqueous layer was extracted with dichloromethane(2×100 mL). The combined organic layer was washed with Na₂S₂O₄ (3×100mL, 5%) to remove iodine and dried over anhydrous magnesium sulfate. Thesolution was filtered and then concentrated under vacuum. The cruderesidue was purified by a silica gel column, eluted with 0.5-1% ethylacetate in petroleum ether to afford5-fluoro-2-(iodomethyl)-2,3-dihydro-1-benzofuran as a yellow oil (5 g,54%); ¹H NMR (300 MHz, DMSO): δ 7.03-7.08 (dd, J=5.7 Hz, 8.4 Hz, 1H),6.93-6.86 (dt, J=2.7 Hz, 8.7 Hz, 1H), 6.76-6.70 (m, 1H), 4.88-4.79 (m,1H), 3.49-3.60 (m, 2H), 3.41-3.32 (dd, J=7.2 Hz, 16.5 Hz, 1H), 2.96-2.88(dd, J=7.2 Hz, 16.5 Hz, 1H).

Step 4. Formation of1-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazine

Into a 100 ml round-bottomed flask containing 40 ml of acetonitrile wasadded 5-Fluoro-2-iodomethyl-2,3-dihydro-benzofuran (5.7 g, 20.5 mmol),piperazine (6.6 g, 76.6 mmol, 4 eq), and potassium carbonate (4.2 g,30.4 mmol, 1.5 eq). The mixture was stirred at room temperature for 4hours. The reaction contents were diluted with water and then extractedwith 3×200 ml of ethyl acetate. The organic layers were combined, driedover sodium sulfate, filtered, and then concentrated under vacuum. Thecrude material was then chromatography on silica gel usingmethanol/dichloromethane to elute. The product containing fractions werethen concentrated under vacuum to provide 2.2 g (45%) of the substitutedpiperazine as a dark red oil.

Step 5. Formation of4-[[4-(3-[4-[(5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-oxopropoxy)cyclohexyl]amino]-2-(trifluoromethyl)benzonitrile(#83)

To a solution of2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]aceticacid (216 mg, 0.63 mmol, 1.5 eq) in dichloromethane (25 ml) was addedEDAC.HCl (122 mg, 0.64 mmol, 1.5 eq), HOBt (86 mg, 0.64 mmol, 1.5 eq),triethylamine (128 mg, 1.26 mmol, 3 eq) and1-[(5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazine (100 mg,0.42 mmol) at room temperature. The solution was stirred at roomtemperature overnight, diluted with dichloromethane (150 ml), and washedwith water (80 ml). The organic layer was dried over anhydrous magnesiumsulfate, filtered, and concentrated under vacuum. The crude material waspurified by silica gel chromatography using 1-2% methanol indichloromethane to elute. The product-containing fractions were combinedand concentrated under vacuum to afford4-[[4-(3-[4-[(5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-oxopropoxy)cyclohexyl]amino]-2-(trifluoromethyl)benzonitrile as a white solid (0.18 g, 69%); (ES, m/z): [M+H]⁺ 561.20;¹H NMR (300 MHz, CDCl₃): δ 7.56 (d, J=8.7 Hz, 1H), 6.81-6.92 (m, 3H),6.64-6.71 (m, 2H), 5.13 (broad s, 1H), 4.29 (d, J=7.8 Hz, 1H), 4.21 (s,2H), 3.67-3.77 (m, 3H), 3.34-3.47 (m, 3H), 2.92-2.99 (dd, J=−8.1 Hz,−15.9 Hz, 1H), 2.51-2.89 (m, 5H), 2.15-2.25 (broadened d, J=9.9 Hz, 4H),1.41-1.48 (m, 3H), 1.21-1.32 (m, 3H).

Example 17 Preparation of Compound 80

Step 1. Formation of 1-allyloxy-4-fluoro-benzene

Into a 1 L round-bottomed flask containing 500 ml of acetonitrile wasadded 4-fluorophenol (30.0 g, 267.6 mmol), 3-bromoprop-1-ene (41.7 g,344.7 mmol, 1.3 eq), and potassium carbonate (55 g, 398 mmol, 1.5 eq).The mixture was stirred for 3.5 hours at 60° C. (oil bath). The solidswere filtered off and the filtrate was concentrated under vacuum leaving25.0 grams of the crude product as a yellow oil; 61%.

Step 2. Formation of 2-allyl-4-fluoro-phenol

In a 250 ml round-bottomed flask, 1-fluoro-4-(prop-2-en-1-uloxy)benzene(23.0 g, 151 mmol) was heated at 260° C. for 5 hours. The crude productwas purified by silica gel chromatography using petroleum ether/ethylacetate to elute. The product-containing fractions were concentratedunder vacuum to provide 18.0 grams (78%) of a yellow oil.

Step 3. Formation of (5-fluoro-2,3-dihydro-benzofuran-2-yl)-methanol

Into a 500 ml round-bottomed flask that contained a solution of2-allyl-4-fluoro-phenol (10.0 g, 65.7 mmol) in 300 ml of chloroform wasadded m-CPBA (11 g, 64 mmol, ˜0.96 eq). The mixture was heated at 60° C.(oil bath) for 6 hours. The contents were cooled to room temperature andthe solids were filtered off and washed with 3×20 ml of chloroform. Thefiltrate was washed with saturated aqueous NaHCO₃ (2×100 mL) to removetraces of m-CPBA, dried over magnesium sulfate, filtered, and thenconcentrated under vacuum. The crude residue was then chromatographed onsilica gel using petroleum ether/ethyl acetate to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford 8.5 grams of the alcohol as a yellow oil (77%); ¹H NMR (300MHz, CDCl₃): δ 6.91-6.88 (m, 1H), 6.84-6.78 (m, 1H), 6.72-6.68 (m, 1H),4.99-4.90 (m, 1H), 3.90-3.85 (dd, J=3.3 Hz, 12 Hz, 1H), 3.78-3.70 (dd,J=3.3 Hz, 12 Hz, 1H), 3.29-3.21 (dd, J=9.3 Hz, 15.9 Hz, 1H), 3.01-3.08(dd, J=7.5 Hz, 15.9 Hz, 1H).

Step 4. Formation of 5-fluoro-2,3-dihydro-benzofuran-2-carboxylic acid

To a 500 ml round-bottomed flask that contained a solution of(5-fluoro-2,3-dihydro-benzofuran-2-yl)-methanol (3.0 g, 17.8 mmol) in100 ml of acetonitrile was added a solution of potassium bicarbonate(7.14 g, 71.4 mmol, 4 eq) in 30 ml of water. The mixture was cooled to0° C. and TEMPO (56 mg, 0.36 mmol, 2 mol %) was added, followed by thedropwise addition of NaOCl_((aq)) (60 ml, 1.1 eq). The mixture was thenstirred for 1.5 hours at room temperature. The pH was then adjusted to 4using aqueous hydrogen chloride (3N). The mixture was then extractedwith 3×80 ml of ethyl acetate. The organic fractions were combined,dried over magnesium sulfate, filtered and then concentrated undervacuum to provide 2.0 grams of the crude product as a yellow solid.

Step 6. Formation of4-(5-fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester

In a 250 ml round-bottomed flask containing a solution of5-fluoro-2,3-dihydro-benzofuran-2-carboxylic acid (1.8 g, 9.9 mmol) in100 ml of dichloromethane was added EDAC.HCl (2.85 g, 14.9 mmol, 1.5eq), HOBt (2.00 g, 14.8 mmol, 1.5 eq), triethylamine (2.00 g, 19.8 mmol,2.0 eq), and t-butyl piperazine-1-carboxylate (2.20 g, 11.8 mmol, 1.2eq). The solution was stirred overnight at room temperature beforediluting with 50 ml of water. The crude product was then extracted fromthe mixture using 3×50 ml of dichloromethane. The organic layers werecombined, dried over magnesium sulfate, filtered, and then concentratedunder vacuum. The crude residue was purified by silica gelchromatography using ethyl acetate/petroleum ether to elute. Theproduct-containing fractions were combined and concentrated under vacuumto afford 1.8 grams of the desired amide as a light yellow solid (52%);¹H NMR (300 MHz, CDCl₃): δ 6.92 (dd, J=2.4 Hz, 7.8 Hz, 1H), 6.79 (m,1H), 6.69 (dd, J=4.2 Hz, 8.7 Hz, 1H), 5.40 (dd, J=7.2 Hz, 9.9 Hz, 1H),3.78-3.91 (m, 3H), 3.46-3.67 (m, 5H), 3.26-3.39 (m, 2H), 1.49 (s, 1H).

Step 7. Formation of(5-fluoro-2,3-dihydro-benzofuran-2-yl)-piperazin-1-yl-methanone

In a 100 ml round-bottomed flask was added4-(5-Fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazine-1-carboxylicacid tert-butyl ester (1.8 g, 5.1 mmol), 50 ml of dichloromethane, and 2ml of trifluoroacetic acid. The solution was stirred at room temperatureovernight. The solution was made basic with the addition of saturatedaqueous sodium bicarbonate. The mixture was then extracted with 4×50 mlof dichloromethane. The organic fractions were combined, dried overmagnesium sulfate, filtered, and concentrated under vacuum to afford 1.2grams of the desired amine as a brown oil (94%).

Step 8. Formation of1-[4-(5-fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone(#80)

In a 50 ml round-bottomed flask containing a solution of(5-fluoro-2,3-dihydro-benzofuran-2-yl)-piperazin-1-yl-methanone (76 mg,0.30 mmol, 1.1 eq) in 30 ml of dichloromethane was added EDAC.HCl (76mg, 0.40 mmol, 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq), triethylamine(56 mg, 0.55 mmol, 2.0 eq), and[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid(100 mg, 0.28 mmol). The solution was stirred overnight at roomtemperature before diluting with 30 ml of water. The crude product wasthen extracted from the mixture using 3×30 ml of ethyl acetate. Theorganic layers were combined, dried over magnesium sulfate, filtered,and then concentrated under vacuum. The crude residue was purified bysilica gel chromatography using ethyl acetate/dichloromethane to elute.The product-containing fractions were combined and concentrated undervacuum to afford 72 mg of the desired amide as a yellow solid (44%); ¹HNMR (300 MHz, CDCl₃): δ 8.04 (d, J=6.6 Hz, 1H), 6.95 (d, J=5.4, 1H),6.83 (m, 2H), 6.66 (m, 2H), 5.43 (m, 1H), 4.25 (s, 1H), 3.75-3.95 (m,4H), 3.27-3.80 (m, 8H), 2.12-2.22 (m, 4H), 1.50 (dd, J=7.8 Hz, 16.8 Hz,2H), 1.31 (dd, J=7.8 Hz, 16.8 Hz, 2H).

Example 18 Preparation of Compound 79

Step 1. Formation of 1-chloro-4-(prop-2-en-1-yloxy)benzene

To a solution of 4-chlorophenol (30 g, 233 mmol) in acetonitrile (100ml) was added potassium carbonate (48.1 g, 349 mmol, 1.5 eq) and allylbromide (36.28 g, 299.9 mmol, 1.3 eq) dropwise with stirring for 5 hoursat 50° C. in an oil bath. The solids were filtered out and the liquidwas concentrated under vacuum to afford1-chloro-4-(prop-2-en-1-yloxy)benzene as yellow oil (34 g, 86%); ¹H NMR(300 MHz, CDCl₃): δ 7.20-7.25 (m, 2H), 6.81-6.86 (m, 2H), 5.96-6.09 (m,1H), 5.27-5.44 (m, 2H), 4.49-4.51 (m, 2H).

Step 2. Formation of 4-chloro-2-(prop-2-en-1-yl)phenol

1-chloro-4-(prop-2-en-1-yloxy)benzene (34 g, 202 mmol) was stirred for 7hours at 260° C. The reaction mixture was purified via silica gelchromatography using 3% ethyl acetate in petroleum ether to elute. Theproduct-containing fractions were combined and concentrated to afford4-chloro-2-(prop-2-en-1-yl)phenol as light brown oil (17 g, crude); ¹HNMR (300 MHz, CDCl₃): δ 7.03-7.09 (m, 2H), 6.75 (d, J=3.0 Hz, 1H),5.92-6.05 (m, 1H), 5.13-5.20 (m, 2H), 3.37 (d, J=6.3 Hz, 2H).

Step 3. Formation of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol

To a solution of 4-chloro-2-(prop-2-en-1-yl)phenol (17 g, crude,nominally 101 mmol) in chloroform (100 ml) was added mCPBA (17.4 g, 101mmol, 1 eq) with stirring for 1 h at 50° C. in an oil bath. Then thereaction mixture was concentrated under vacuum and re-dissolved in MeOH(100 ml). Potassium carbonate (27.6 g, 200 mmol, 2 eq) was added and themixture was stirred for 5 hours at 50° C. The solids were filtered offand the filtrate was concentrated under vacuum. The crude material waspurified by silica gel chromatography using 3% ethyl acetate inpetroleum ether to elute. The product-containing fractions were combinedand concentrated under vacuum to afford(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol as yellow oil (6.15 g);¹H NMR (300 MHz, CDCl₃): δ 7.00-7.18 (m, 2H), 6.80 (d, J=8.7 Hz, 1H),4.88-4.97 (m, 1H), 3.85-3.90 (m, 1H), 3.70-3.79 (m, 1H), 3.19-3.27 (dd,J=9.3 Hz, 15.9 Hz, 1H), 2.98-3.05 (dd, J=7.5 Hz, 15.9 Hz, 1H), 2.10(broad s, 1H).

Step 4. Formation of 5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid

To a solution of (5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanol (2 g,11 mmol), KHCO₃ (4.32 g, 43 mmol, 4 eq) and TEMPO (20 mg, 0.13 mmol, 0.1eq) in water (8 ml) and CH₃CN (18 ml) was added NaOCl (20 ml, aq. 15%,˜4 eq) dropwise with stirring at 0° C. and stirred for 1 hour. Themixture was diluted with water (200 ml) and adjusted to pH ˜4 withhydrogen chloride (2N). After extraction with ethyl acetate (3×200 ml),the organic layers were combined, washed with brine (200 ml), dried overanhydrous sodium sulfate, filtered, and then concentrated under vacuum.The crude material was purified by silica gel chromatography using 1%methanol in dichloromethane to elute. The product-containing fractionswere combined and concentrated under vacuum to afford5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid as a yellow solid(1.6 g, 74%). ¹H NMR (300 MHz, CDCl₃): δ 7.05-7.22 (m, 2H), 6.83 (d,J=8.4 Hz, 1H), 5.20-5.30 (m, 1H), 3.56-3.65 (m, 1H), 3.33-3.45 (m, 1H)Step 5. Formation of tert-butyl4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylate.

To a solution of 5-chloro-2,3-dihydro-1-benzofuran-2-carboxylic acid (1g, 5 mmol) in N,N-dimethylformamide (10 ml) was added EDAC.HCl (1.45 g,7.56 mmol, 1.5 eq), HOBt (1.02 g, 7.55 mmol, 1.5 eq), triethylamine(1.52 g, 15.0 mmol, 3 eq) and tert-butyl piperazine-1-carboxylate (935mg, 5.02 mmol, 1 eq). The resulting solution was stirred overnight atroom temperature, quenched with water (200 ml), and then extracted withethyl acetate (3×200 ml). The combined organic layer was washed withbrine (3×100 ml), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The crude material was purified by silica gelchromatography using 10%-20% ethyl acetate in petroleum ether to elute.The product-containing fractions were combined and concentrated undervacuum to afford tert-butyl4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylateas a off-white solid (1.2 g, 65%). (ES, m/z): [M+H]⁺ 367; ¹H NMR (300MHz, CDCl₃): δ 7.05-7.22 (m, 2H), 6.72 (d, J=8.4 Hz, 1H), 5.38-5.45 (m,1H), 3.75-3.90 (m, 3H), 3.25-3.70 (m, 7H), 1.50 (s, 9H).

Step 6. Formation of1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine

A solution of tert-butyl4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylate(400 mg, 1.09 mmol) in dichloromethane (5 ml) was treated withtrifluoroacetic acid (1 ml). The resulting solution was stirred for 2 hat room temperature and then concentrated under vacuum to give aresidue. The crude material was dissolved into water (20 ml) and the pHwas adjusted to ˜8 using aqueous sodium bicarbonate. The mixture wasextracted with ethyl acetate (3×100 ml). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to afford1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine as lightyellow oil (280 mg, 96%). (ES, m/z): [M+H]⁺ 267; ¹H NMR (300 MHz,CDCl₃): δ 7.20 (s, 1H), 7.05-7.11 (m, 1H), 6.70 (d, J=8.4 Hz, 1H),5.46-5.55 (m, 1H), 3.85-3.95 (m, 3H), 3.53-3.63 (m, 2H), 3.25-3.35 (m,1H), 2.90-3.05 (m, 4H).

Step 7. Formation of1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one (#79)

To a solution of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]aceticacid (100 mg, 0.28 mmol) in dichloromethane (20 ml) was added EDAC.HCl(80 mg, 0.42 mmol 1.5 eq), HOBt (56 mg, 0.41 mmol, 1.5 eq),triethylamine (84 mg, 0.83 mmol, 3 eq) and1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazine (74 mg,0.28 mmol, 1 eq). The resulting solution was stirred overnight at roomtemperature and then concentrated under vacuum. The crude residue waspurified by silica gel chromatography using 5-20% ethyl acetate indichloromethane to elute. The product-containing fractions were combinedand concentrated under vacuum to afford1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)carbonyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-oneas a yellow solid (34.9 mg, 19%). (ES, m/z): [M+H]+ 611.25; ¹H NMR (300MHz, CDCl₃): δ 8.00 (d, J=9.0 Hz, 1H), 7.18 (s, 1H), 7.07 (d, J=8.4 Hz,1H), 6.85 (d, J=2.1 Hz, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.63 (dd, J=2.1 Hz,9.0 Hz, 1H), 5.42 (dd, J=7.5 Hz, 9.0 Hz, 1H), 4.23 (s, 2H), 3.82-3.98(m, 4H), 3.30-3.70 (m, 8H), 2.10-2.20 (m, 4H), 1.42-1.58 (m, 2H),1.20-1.40 (m, 2H).

Example 19 Preparation of Compound 84

Step 1. Formation of 1-(prop-2-en-1-yloxy)-4-(trifluoromethyl)benzene

To a solution of 4-(trifluoromethyl)phenol (50 g, 308 mmol) in CH₃CN(600 ml) was added potassium carbonate (64 g, 463 mmol, 1.5 eq) andallyl bromide (48 g, 397 mmol, 1.3 eq) with stirring for overnight at50° C. in an oil bath. The solids were filtered off and the filtrate wasconcentrated to a minimum volume, which was diluted by water (200 ml)and extracted with ethyl acetate (3×100 ml). The combined organic layerswere washed with brine (2×200 ml), dried over anhydrous magnesiumsulfate, filtered, and then concentrated under vacuum to afford1-(prop-2-en-1-yloxy)-4-(trifluoromethyl)benzene as yellow oil (35 g,56%), ¹H NMR (300 MHz, CDCl₃): δ 7.52 (d, J=8.7 Hz, 2H), 6.96 (d, J=8.7Hz, 2H), 5.98-6.11 (m, 1H), 5.30-5.46 (m, 2H), 4.57-4.58 (m, 2H).

Step 2. Formation of 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol

A solution of 1-(prop-2-en-1-yloxy)-4-(trifluoromethyl)benzene (30 g,148 mmol) in dichloromethane (250 ml) was treated with 1N solution ofBCl₃ (163 ml, 163 mmol, 1.1 eq) in dichloromethane for 2.5 h at −20° C.under an inert atmosphere of nitrogen. The reaction mixture was thenquenched with ice-water (200 ml) and the organic layer was separatedout. The aqueous layer was extracted further with dichloromethane (3×200ml) and the combined organic layer was washed with saturated aqueoussodium bicarbonate (200 ml) and then dried over anhydrous magnesiumsulfate. The solution was filtered and then concentrated under vacuum toafford 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol as colorless oil (25g, 83%); ¹H NMR (300 MHz, CDCl₃): δ 7.38 (d, J=7.5 Hz, 2H), 6.86 (t,J=8.7 Hz, 1H), 5.94-6.07 (m, 1H), 5.60 (s, 1H), 5.15-5.22 (m, 2H), 3.43(d, J=6.6 Hz, 2H).

Step 3. Formation of2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran

To a solution of 2-(prop-2-en-1-yl)-4-(trifluoromethyl)phenol (4 g, 20mmol) in dichloromethane (50 ml) was added SnCl₄ (2.6 g, 10.0 mmol, 0.5eq) dropwise and iodine (5.03 g, 19.8 mmol, 1 eq) with stirring for 6 hat room temperature. The reaction mixture was diluted withdichloromethane (200 ml) and quenched by the addition of water (100 ml).The organic layer was separated and the pH value of the aqueous layerwas adjusted to ˜8 with aqueous sodium bicarbonate. The aqueous layerwas extracted further with dichloromethane (3×100 ml). The organiclayers were combined, washed with aqueous Na₂S₂O₄ (5%, 100 ml) to removeremaining iodine, dried over anhydrous magnesium sulfate, filtered, andthen concentrated under vacuum. The crude material was purified bysilica gel chromatography using 1% ethyl acetate in petroleum ether toelute. The product-containing fractions were combined and concentratedunder vacuum to afford2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran as colorlessoil (2.8 g, 43%); ¹H NMR (300 MHz, CDCl₃): δ 7.39 (d, J=5.7 Hz, 2H),6.83 (d, J=8.7 Hz, 1H), 4.91-5.00 (m, 1H), 3.34-3.48 (m, 3H), 3.05-3.12(m, 1H).

Step 4. Formation of1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine

To a solution of2-(iodomethyl)-5-(trifluoromethyl)-2,3-dihydro-1-benzofuran (2.8 g, 8.5mmol) in CH₃CN (40 ml) was added potassium carbonate (2.36 g, 17.1 mmol,2 eq) and piperazine (2.94 g, 34.1 mmol, 4 eq) at room temperature. Themixture was heated at reflux for 3 h, then solids were filtered out andthe filtrate was concentrated under vacuum. The crude material waspurified by silica gel chromatography using 1-2.5% methanol indichloromethane to elute. The product-containing fractions were combinedand concentrated under vacuum to afford1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazineas light yellow oil (1.25 g, 51%); (ES, m/z): [M+H]⁺ 287; ¹H NMR (300MHz, CDCl₃): δ 7.37 (d, J=9.0 Hz, 2H), 6.83 (d, J=8.4 Hz, 1H), 5.00-5.10(m, 1H), 3.26-3.35 (m, 1H), 2.96-3.04 (m, 1H), 2.88-2.95 (m, 4H),2.78-2.80 (m, 1H), 2.54-2.69 (m, 4H).

Step 5. Formation of4-([4-[2-oxo-2-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethoxy]cyclohexyl]amino)-2-(trifluoromethyl)benzonitrile(#84)

To a solution of 2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetic acid (100 mg, 0.29 mmol) indichloromethane (30 ml) was added EDAC.HCl (84.2 mg, 0.44 mmol, 1.5 eq),HOBt (59.2 mg, 0.44 mmol, 1.5 eq), triethylamine (59.1 mg, 0.58 mmol, 2eq) and1-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazine(92.0 mg, 0.32 mmol, 1.1 eq). The reaction mixture was stirred overnightat room temperature and then quenched by the addition of water (30 ml).The crude product was extracted with ethyl acetate (3×20 ml). Theorganic layers were combined, dried over anhydrous magnesium sulfate,filtered, and then concentrated under vacuum. The crude material waspurified by Pre-TLC with 20% ethyl acetate in dichloromethane to afford4-([4-[2-oxo-2-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethoxy]cyclohexyl]amino)-2-(trifluoromethyl)benzonitrileas a white solid (76 mg, 43%); (ES, m/z): [M+H]⁺ 611.30; ¹H NMR (300MHz, CDCl₃): δ 7.55 (d, J=8.7 Hz, 1H), 7.42 (m, 2H), 6.81-6.86 (m, 2H),6.64-6.68 (dd, J=2.1 Hz, 8.4 Hz, 1H), 5.08-5.13 (m, 1H), 4.29 (d, J=7.8Hz, 1H), 4.21 (s, 2H), 3.65-3.78 (m, 3H), 3.30-3.48 (m, 3H), 3.01-3.06(dd, J=8.4 Hz, 15.9 Hz, 2H), 2.51-2.90 (m, 4H), 2.10-2.19 (m, 4H),1.44-1.58 (m, 3H), 1.21-1.33 (m, 3H).

Example 20 Preparation of Compound 75

Step 1. Formation of ethyl [(naphthalen-2-yl)carbamoyl]formate

To a solution of naphthalen-2-amine (2 g, 14.0 mmol) in dichloromethane(30 ml) was added triethylamine (4.24 g, 41.9 mmol, 3 eq). Then, ethyl2-chloro-2-oxoacetate (1.92 g, 14.1 mmol, 1 eq) was added dropwise tothe solution kept at 0-5° C. using an ice-bath. The resulting solutionwas allowed to warm to room temperature while stirring. The reaction wasthen quenched by the addition of water (50 ml), the product wasextracted with dichloromethane (2×50 ml), and the organic layers werecombined. The organic solution was washed with saturated aqueous sodiumchloride (50 ml), dried over anhydrous sodium sulfate, filtered, andthen concentrated under vacuum to afford ethyl[(naphthalen-2-yl)carbamoyl]formate as a black solid (3 g, 88%). (ES,m/z) [M+H]⁺ 244; ¹H NMR (300 MHz, CDCl₃): δ 9.06 (broad s, 1H), 8.32 (d,J=1.8 Hz, 1H), 7.72-7.88 (m, 3H), 7.59 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.53(m, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H).

Step 2. Formation of lithio [(naphthalen-2-yl)carbamoyl]formate

To a solution of ethyl [(naphthalen-2-yl)carbamoyl]formate (320 mg, 1.32mmol) in tetrahydrofuran (15 ml) and methanol (15 ml) was added asolution of lithium hydroxide (31.6 mg, 1.32 mmol, 1 eq) in water (1ml). The resulting solution was stirred for 20 min at room temperatureand then concentrated under vacuum to afford lithio[(naphthalen-2-yl)carbamoyl]formate as a black solid (290 mg, crude). ¹HNMR (300 MHz, DMSO): δ 10.46 (s, 1H), 8.44 (s, 1H), 7.80-7.90 (m, 4H),7.33-7.50 (m, 2H).

Step 3. Formation of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetamide

To a heated solution (60° C.) of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]aceticacid (300 mg, 0.83 mmol) in tetrahydrofuran (25 ml) was added CDI (300mg, 1.85 mmol, 2.2 eq) at reflux and then stirred for 1 hour at 60° C.(oil bath temperature). The resulting solution was poured into ammonia(25 ml) at room temperature and stirred for an additional 1 hour. Thecontents were diluted with water (100 ml) and the resulting mixture wasextracted with ethyl acetate (3×100 ml). The organic layers werecombined, washed with saturated aqueous sodium chloride (100 ml), driedover anhydrous sodium sulfate, filtered, and then concentrated undervacuum to afford2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetamideas yellow solid (220 mg, 74%). (ES, m/z) [M+H]⁺ 362; ¹H NMR (300 MHz,DMSO): δ 8.06 (d, J=9.0 Hz, 1H), 7.48 (d, J=7.8 Hz, 1H), 7.27 (d, J=4.2Hz, 1H), 7.07 (s, 2H), 6.85 (dd, J=2.4 Hz, 9.3 Hz, 1H), 3.82 (s, 2H),3.40-3.55 (m, 2H), 1.90-2.10 (m, 4H), 1.10-1.50 (m, 4H)

Step 4. Formation ofN-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl)aniline

A solution of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]acetamide(220 mg, 0.61 mmol) in borane/THF (1M, 10 ml) was stirred for 10 minutesat 70° C. in an oil bath. The solution was quenched by the addition ofaqueous hydrogen chloride (2 ml of a 1M solution), diluted with water(15 ml), and extracted with ethyl acetate (3×15 ml). The aqueous layerwas adjusted to pH ˜8 with saturated aqueous sodium bicarbonate andextracted further with dichloromethane (3×20 ml). The organic layerswere combined and concentrated under vacuum to affordN-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl)aniline asyellow oil (180 mg, 85%). (ES, m/z) [M+H]⁺ 348; ¹H NMR (300 MHz, DMSO):δ 8.06 (d, J=Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.07 (s, 1H), 6.84 (dd,J=2.7 Hz, 7.8 Hz, 1H), 3.39-3.55 (m, 6H), 2.65-2.70 (t, J=5.7 Hz, 2H),1.90-2.10 (m, 4H), 1.15-1.40 (m, 4H).

Step 5. Formation ofN-(naphthalen-2-yl)-N-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]ethanediamide(#75)

To a solution of lithio [(naphthalen-2-yl)carbamoyl]formate (172 mg,0.78 mmol, 1.5 eq) in N,N-dimethylformamide (15 ml) was addedN-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl) aniline (180mg, 0.52 mmol), EDAC.HCl (149 mg, 0.78 mmol, 1.5 eq), HOBt (105 mg, 0.78mmol, 1.5 eq) and triethylamine (157 mg, 1.55 mmol, 3 eq). The resultingsolution was stirred for 24 hours at room temperature. The solution wasdiluted with ethyl acetate (200 ml), washed with water (3×100 ml), andthen washed with saturated aqueous sodium chloride (100 ml). The organiclayer was then dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The crude material was purified by silica gelchromatography using 1% methanol in dichloromethane to elute. Theproduct-containing fractions were combined and concentrated under vacuumto affordN-(naphthalen-2-yl)-N-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]ethanediamideas a yellow solid (48.6 mg, 17%). (ES, m/z) [M+H]⁺ 545.25; ¹H NMR (300MHz, CDCl₃): δ 9.45 (s, 1H), 8.33 (d, J=2.1 Hz, 1H), 8.02 (d, J=9.0 Hz,1H), 7.80-7.98 (m, 4H), 7.60 (dd, J=2.1 Hz, 8.7 Hz, 1H), 7.40-7.55 (m,2H), 6.85 (d, J=2.4 Hz, 1H), 6.63 (dd, J=2.4 Hz, 9.0 Hz, 1H), 4.47 (d,J=7.5 Hz, 1H), 3.55-3.70 (m, 4H), 3.30-3.45 (m, 2H), 2.08-2.22 (m, 4H),1.40-1.53 (m, 2H), 1.20-1.37 (m, 2H).

2-methyl-3-[4-(naphthalen-2-yl)piperazin-1-yl]-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)propan-1-one(Compound 13)

(ES, m/z): [M+H]⁺ 570; ¹H NMR (300 MHz, DMSO-d6): δ 8.04 (d, J=9.0 Hz,1H), 7.76-7.68 (m, 3H), 7.49 (d, J=7.5 Hz, 1H), 7.35-7.40 (t, J=7.2 Hz,2H), 7.22-7.27 (t, J=7.2 Hz, 1H), 7.09-7.15 (m, 2H), 6.90 (dd, J=9.3,2.1 Hz, 1H), 4.30-4.40 (m, 1H), 3.98-4.11 (m, 1H), 3.68-3.85 (m, 1H),3.05-3.26 (m, 5H), 2.75-2.96 (m, 1H), 2.54-2.66 (m, 5H), 2.21-2.35 (m,1H), 1.84-2.05 (m, 2H), 1.14-1.48 (m, 2H), 1.95-1.09 (m, 3H). One protonis not apparent (may be hidden under DMSO or water peak).

3-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]-2-methyl-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperi-din-1-yl)propan-1-one(#016)

(ES, m/z): [M+H]⁺ 588.55; ¹H NMR (300 MHz, CDCl₃): δ 8.01-8.04 (t, J=5.4Hz, 1H), 7.66-7.70 (m, 2H), 7.35-7.38 (m, 1H), 7.30 (d, J=6.3 Hz, 1H),7.19-7.24 (m, 1H), 7.12 (s, 1H), 6.90 (s, 1H), 6.66-6.69 (t, J=7.2 Hz,1H), 4.50-4.68 (overlapping m, 2H), 4.05-4.09 (t, J=10.5 Hz, 1H),3.66-3.70 (m, 1H), 3.30 (s, 5H), 3.10 (s, 1H), 2.86-2.95 (m, 2H),2.60-2.73 (m, 4H). 2.40-2.49 (m, 1H), 2.12-2.49 (m, 2H), 1.45-1.61 (m,2H), 1.18 (d, J=4.5 Hz, 3H).

Compound 91:2-methyl-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)-3-[4-(quinolin-2-yl)piperazin-1-yl]propan-1-one

(ES, m/z): [M+H]⁺ 571.15; ¹H NMR (300 MHz, CDCl₃): δ 7.98-8.05 (m, 1H),7.88 (d, J=9.3 Hz, 1H), 7.70 (d, J=8.1 Hz, 1H), 7.61 (d, J=7.8 Hz, 1H),7.55 (dd, J=7.5, 7.8 Hz, 1H), 7.22-7.25 (m, 1H), 6.96 (d, J=9.3 Hz, 1H),6.89 (s, 1H), 6.64 (d, J=8.1 Hz, 1H), 4.60-4.64 (br m, 2H), 4.07 (dd,J=14.1, 17.4 Hz, 1H), 3.76 (br s, 4H), 3.73 (m, 1H), 3.02-3.35(overlapping m, 2H), 2.90 (overlapping m, 2H), 2.65 (br s, 4H), 2.45 (d,J=10.5 Hz, 1H), 2.01-2.20 (m, 2H), 1.38-1.58 (m, 2H), 1.15 (d, J=4.8 Hz,3H).

Example 21 Preparation of Compound 92

Steps 1-6

The formation of 2-piperazin-1-yl-6-trifluoromethyl-quinoline wasperformed as was described in the synthesis shown for compound 89. Theconversion to2-methyl-3-[4-(6-trifluoromethyl-quinolin-2-yl)-piperazin-1-yl]-propionicacid was performed in a manner analogous to what was described in thesynthetic scheme for compound 13.

Step 7. Formation of2-methyl-1-(4-(4-nitro-3-(trifluoromethyl)phenylamino)piperidin-1-yl)-3-(4-(6-(trifluoromethyl)quinolin-2-yl)piperazin-1-yl)propan-1-one(#92)

To a solution of 2-methyl-3-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]propanoic acid (100 mg, 0.27 mmol) indichloromethane (20 ml) was added EDAC.HCl (79 mg, 0.41 mmol, 1.5 eq.),1H-1,2,3-benzotriazol-1-ol (55.2 mg, 0.41 mmol, 1.5 eq.), triethylamine(82.6 mg, 0.82 mmol, 3 eq.) andN-[4-nitro-3-(trifluoromethyl)phenyl]piperidin-4-amine (94.5 mg, 0.33mmol, 1.2 eq.). The resulting solution was stirred overnight at roomtemperature and then quenched by the addition of water (50 ml) andextracted with dichloromethane (3×30 ml). The organic layers werecombined, dried over anhydrous sodium sulfate, and concentrated undervacuum to give a residue, which was purified by Prep-TLC with 5%methanol in dichloromethane to afford of2-methyl-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)-3-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]propan-1-oneas a yellow solid (111.2 mg, 64%). (ES, m/z): [M+H]⁺ 639.40; ¹H NMR (300MHz, CDCl₃): δ 7.95-8.08 (m, 1H), 7.72 (overlapping m, 2H), 7.01 (d,J=9.3 Hz, 1H), 6.89 (m, 1H), 6.65 (m, 1H), 4.49-4.70 (m, 2H), 4.08 (m,1H), 3.72-3.85 (br m, 5H), 3.65 (m, 1H), 3.08 (br s, 1H), 2.88 (br m,2H), 2.68 (br s, 3H), 2.38 (m, 1H), 2.07-2.20 (overlapping m, 2H), 1.47(m, 2H), 1.13 (br s, 3H).

Compound 93:3-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-methyl-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)propan-1-one

(ES, m/z): [M+H]⁺ 605.15; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.80 (d, J=9.3 Hz, 1H), 7.60 (overlapping d, 2H), 7.46 (dd, J=2.1,9.0 Hz, 1H), 6.98 (d, J=9.0 Hz, 1H), 6.88 (s, 1H), 6.65 (d, J=9.0 Hz,1H), 4.55-4.67 (overlapping m, 2H), 4.06-4.10 (m, 1H), 3.63-3.82 (m,5H), 3.22-3.26 (m, 1H), 3.01-3.10 (m, 1H), 2.83-2.97 (m, 2H), 2.63 (s,4H), 2.39-2.43 (m, 1H), 2.01-2.14 (m, 2H), 1.42-1.50 (m, 2H), 1.14 (d,J=5.1 Hz, 3H).

Compound 100:3-[4-(6-fluoroquinolin-2-yl)piperazin-1-yl]-2-methyl-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)propan-1-one

(ES, m/z): [M+H]⁺ 589.15; ¹H NMR (300 MHz, CDCl₃): δ 8.00 (d, J=8.7 Hz,1H), 7.84 (d, J=9.3 Hz, 1H), 7.64-7.69 (m, 1H), 7.25-7.34 (m, 2H), 6.98(d, J=9.0 Hz, 1H), 6.89 (s, 1H), 6.64 (d, J=8.7 Hz, 1H), 4.60 (m, 2H),4.09 (m, 1H), 3.55-3.81 (overlapping m, 5H), 3.00-3.40 (overlapping m,2H), 2.90 (br m, 2H), 2.64 (br s, 4H), 2.42 (m, 1H), 2.12 (m, 2H),1.38-1.55 (br m, 2H), 1.14 (d, J=6.3 Hz, 3H).

Compound 101:2-methyl-3-[4-(4-methylquinolin-2-yl)piperazin-1-yl]-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)propan-1-one

(ES, m/z): [M+H]⁺ 585.20. ¹H NMR (300 MHz, CDCl₃): δ 8.01 (m, 1H), 7.79(d, J=7.8 Hz, 1H), 7.75 (m, 1H), 7.57 (br s, 1H), 7.30 (m, 1H), 6.90 (s,1H), 6.84 (s, 1H), 6.67 (d, J=9.6 Hz, 1H), 4.52-4.90 (m, 2H), 4.11 (m,1H), 3.76 (br s, 4H), 3.62 (m, 1H), 3.01-3.38 (overlapping m, 2H),2.78-3.00 (m, 2H), 2.65 (br s, 4H), 2.61 (s, 3H), 2.43 (d, J=12.6 Hz,1H), 2.06-2.23 (m, 2H), 1.38-1.63 (m, 2H), 1.14 (d, J=6.0 Hz, 3H).

Compound 102:3-[4-(6-fluoro-4-methylquinolin-2-yl)piperazin-1-yl]-2-methyl-1-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]piperidin-1-yl)propan-1-one

(ES, m/z): [M+H]⁺ 603.15; ¹H NMR (300 MHz, CDCl₃): δ 8.03-7.98 (m, 1H),7.73-7.65 (m, 1H), 7.39 (dd, J=2.4, 2.7 Hz, 1H), 7.31 (˜dd, J=9.3, ˜12.9Hz, 1H—overlaps w/CHCl₃), 6.88 (overlapping s/d, 2H), 6.67 (d, J=6.9 Hz,1H), 4.80-4.51 (m, 2H), 4.15-4.02 (m, 1H), 3.80-3.55 (br overlapping m,5H), 3.38-3.08 (br overlapping m, 2H), 3.05-2.80 (br overlapping m, 2H),2.80-2.60 (m, 3H), 2.55 (s, 3H), 2.43 (m, 1H), 2.25-2.15 (m, 3H),1.50-1.38 (m, 2H), 1.15 (d, J=5.4 Hz, 3H).

Compound 19:2-methyl-3-(4-naphthalen-1-yl-piperazin-1-yl)-1-[4-(4-nitro-3-trifluoromethyl-phenylamino)-piperidin-1-yl]-propan-1-one

(ES, m/z): [M+H]⁺ 570; ¹H NMR (400 MHz, CDCl₃): δ 8.19 (s, 1H), 8.03 (d,J=8.8 Hz, 1H), 7.84 (dd, J=5.6, 3.6 Hz, 1H), 7.57 (d, J=7.6 Hz, 1H),7.40-7.50 (m, 3H), 7.08 (s, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.69 (s, 1H),4.6 (m, 2H), 4.1 (t, J=13.6 Hz, 1H), 3.68 (s, 1H), 2.70-3.40(overlapping m, 11H), 2.52 (m, 1H), 2.15 (m, 2H), 1.50 (overlapping m,2H), 1.20 (d, J=6.0 Hz, 3H).

Compound 20:1-[4-(naphthalen-1-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 557; ¹H NMR (400 MHz, CDCl₃): δ 8.20 (d, J=7.5 Hz,1H); 8.01 (d, J=8.7 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.61 (d, J=8.4 Hz,1H), 7.51 (m, 3H), 7.41 (dd, J=7.2, 8.4 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H),6.85 (s, 1H), 6.6 (d, J=7.8 Hz, 1H), 4.50 (br s, 1H), 4.28 (s, 2H), 3.82(br m, 2H), 3.45 (br m, 3H), 3.13 (m, 4H), 2.17 (d, J=6.6 Hz, 4H), 1.51(m, 2H), 1.25 (m, 2H).

Compound 160:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-(quinolin-4-yl)piperazin-1-yl]ethan-1-one

(ES, m/z): [M+H]⁺ 558.40; ¹H NMR (300 MHz, DMSO-d6): δ 8.72 (d, J=4.8Hz, 1H), 8.11 (t, J=9.3 Hz, 2H), 7.99 (d, J=8.4 Hz, 1H), 7.75 (t, J=8.1Hz, 1H), 7.60 (t, J=8.1 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.07 (d, J=1.5Hz, 1H), 7.02 (d, J=5.1 Hz, 1H), 6.88 (dd, J=9.3, 2.4 Hz, 1H), 4.23 (s,2H), 3.75 (br s, 4H), 3.49-3.40 (m, 2H), 3.19-3.16 (m, 4H), 2.07-1.95(m, 4H), 1.45-1.27 (m, 4H).

Compound 161:1-[4-(4-chloronaphthalen-1-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohe-xyl)oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 591.15; ¹H NMR (300 MHz, CD₃OD): δ 8.33 (dd, J=2.4,6.0 Hz, 1H), 8.26-8.22 (m, 1H), 8.04 (d, J=9.3 Hz, 1H), 7.67-7.59 (m,2H), 7.55 (d, J=7.8 Hz, 1H), 7.14 (d, J=8.1 Hz, 1H), 6.99 (d, J=2.4 Hz,1H), 6.81 (dd, J=2.7, 9.3 Hz, 1H), 4.34 (s, 2H), 3.91-3.71 (m, 2H),3.64-3.45 (m, 4H), 3.12-2.94 (m, 4H), 2.19-2.09 (m, 4H), 1.58-1.46 (m,2H), 1.41-1.30 (m, 2H).

Compound 249:2-[[-4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]propan-1-one

(ES, m/z): [M+H]⁺ 640.10; ¹H NMR (300 MHz, CD₃OD): δ 8.14 (d, J=9.3 Hz,1H), 8.02 (m, 2H), 7.78 (dd, J=9.0, 14.1 Hz, 2H), 7.31 (d, J=9.3 Hz,1H), 6.97 (d, J=2.1 Hz, 1H), 6.78 (d, J=9.3 Hz, 1H), 4.61 (q, J=6.6 Hz,2H), 3.91-3.76 (m, 8H), 3.46 (m, 2H), 2.16-2.02 (m, 4H), 1.58-1.46 (m,2H), 1.42 (d, J=6.9 Hz, 3H), 1.38-1.31 (m, 2H).

Compound 250:1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]propan-1-one

(ES, m/z): [M+H]⁺ 605.95; ¹H NMR (300 MHz, CDCl₃): δ 7.99 (d, J=4.2 Hz,1H), 7.86 (br s, 1H), 7.62 (s, 2H), 7.52 (br s, 1H), 7.05 (d, J=8.7 Hz,1H), 6.84 (d, J=2.4 Hz, 1H), 6.64 (dd, J=2.7, 9.0 Hz, 1H), 4.47-4.38 (m,2H), 3.93-3.79 (overlapping m, 8H), 3.46-3.36 (m, 2H), 2.15 (m, 4H),1.65-1.53 (m, 2H), 1.47 (d, J=6.9 Hz, 3H), 1.32-1.21 (m, 2H).

Compound 251:1-[4-(6-fluoroquinolin-2-yl)piperazin-1-yl]-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]propan-1-one

(ES, m/z): [M+H]⁺ 590.35; ¹H NMR (300 MHz, CD₃OD): δ 8.03 (d, J=9.0 Hz,2H), 7.72-7.67 (m, 1H), 7.39-7.32 (m, 2H), 7.25 (d, J=9.3 Hz, 1H), 6.98(d, J=2.4 Hz, 1H), 6.79 (dd, J=2.7, 9.3 Hz, 1H), 4.61 (q, J=6.9 Hz, 1H),3.90-3.76 (m, 8H), 3.46 (m, 2H), 2.17-2.07 (m, 4H), 1.58-1.50 (m, 2H),1.42 (d, J=6.6 Hz, 3H), 1.38-1.30 (m, 2H).

Compound 252:1-(4-(6-fluoronaphthalen-2-yl)piperazin-1-yl)-2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)propan-1-one

(ES, m/z): [M+H]⁺ 589.15; ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J=9.2 Hz,1H), 7.75 (m, 2H), 7.44-7.41 (m, 2H), 7.28-7.23 (m, 2H), 6.98 (d, J=2.4Hz, 1H), 6.78 (dd, J=6.8, 2.4 Hz, 1H), 4.59 (q, J=6.8 Hz, 1H), 3.95-3.75(m, 4H), 3.50-3.41 (m, 2H), 3.33-3.28 (m, 4H), 2.20-2.05 (m, 4H),1.60-1.40 (m, 2H), 1.48-1.30 (m, 5H).

Compound 310:1-{4-[5-(4-fluoro-phenyl)-2,3-dihydro-benzofuran-2-ylmethyl]-piperazin-1-yl}-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 657; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.27-1.36 (m, 2H),1.40-1.61 (m, 2H), 2.15 (d, J=9.0 Hz, 4H), 2.50-2.71 (m, 5H), 2.83 (dd,J=13.5, 7.8 Hz, 1H), 3.02 (dd, J=15.6, 7.8 Hz, 1H), 3.21-3.51 (m, 3H),3.52-3.80 (m, 4H), 4.21 (s, 2H), 4.52 (d, J=7.6 Hz, 1H), 5.03 (dd,J=8.6, 3.8 Hz, 1H), 6.64 (dd, J=9.1, 2.4 Hz, 1H), 6.75-6.92 (m, 2H),7.09 (t, J=8.7 Hz, 2H), 7.27-7.31 (m, 1H), 7.34 (s, 1H), 7.46 (dd,J=8.6, 5.3 Hz, 2H), 8.02 (d, J=9.0 Hz, 1H).

Compound 261:1-[4-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-{4-[methyl-(4-nitro-3-trifluoromethyl-phenyl)-amino]-cyclohexyloxy}-ethanone

(CI, m/z): [M+H]⁺ 595; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.37-1.52 (m, 2H),1.58-1.73 (m, 2H), 1.85 (d, J=12.6 Hz, 2H), 2.25 (d, J=11.7 Hz, 2H),2.51-2.69 (m, 5H), 2.79 (dd, J=13.5, 7.7 Hz, 1H), 2.91 (s, 3H), 2.97(dd, J=15.9, 8.0 Hz, 1H), 3.27 (dd, J=15.8, 9.0 Hz, 1H), 3.34-3.50 (m,1H), 3.50-3.81 (m, 5H), 4.21 (s, 2H), 4.99 (qd, J=8.2, 3.9 Hz, 1H), 6.69(dd, J=8.7, 4.2 Hz, 1H), 6.73-6.82 (m, 2H), 6.87 (d, J=8.0 Hz, 1H), 6.99(d, J=2.4 Hz, 1H), 8.06 (d, J=9.3 Hz, 1H).

Example 22 Preparation of Compound 68

Steps 1-6

The formation of2-chloro-1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]ethan-1-onewas performed as described in the synthesis of compound 76.

Step 7. Formation of 4-[[tris(propan-2-yl)silyl]oxy]aniline

To a solution of 4-aminophenol (20 g, 183 mmol) in dichloromethane (300ml) was added 1H-imidazole (16.2 g, 240 mmol, 1.3 eq.). Triisopropylchlorosilane (53.1 g, 275 mmol, 1.5 eq.) was added dropwise withstirring for 2 hours at room temperature. The reaction mixture wasfiltered and the filtrate was concentrated under vacuum to give aresidue, which was purified by silica gel column chromatography using25% ethyl acetate in petroleum ether to afford4-[[tris(propan-2-yl)silyl]oxy]aniline as brown oil (34 g, 70%); (ES,m/z): [M+H]⁺266; ¹H NMR (300 MHz, CDCl₃): δ 6.66-6.72 (m, 2H), 6.55-6.59(m, 2H), 3.23 (s, 2H), 1.20-1.30 (m, 3H), 1.13 (s, 18H).

Step 8. Formation of4-nitro-3-(trifluoromethyl)-N-(4-[[tris(propan-2-yl)silyl]oxy]phenyl)aniline

To a solution of 4-[[tris(propan-2-yl)silyl]oxy]aniline (15 g, 56 mmol)in toluene (100 ml) was added 4-bromo-1-nitro-2-(trifluoromethyl)benzene(22.84 g, 84.6 mmol, 1.5 eq.), Pd₂(dba)₃ (2.34 g, 2.3 mmol, 4 mol %),BINAP (710 mg, 1.1 mmol, 2 mol %) and t-BuONa (10.87 g, 113.2 mmol, 2eq.). The mixture was stirred under nitrogen overnight at 100° C. (oilbath). The reaction mixture was concentrated under vacuum to give aresidue, which was purified by silica gel column chromatography using10% ethyl acetate in petroleum ether to afford4-nitro-3-(trifluoromethyl)-N-(4-[[tris(propan-2-yl)silyl]oxy]phenyl)anilineas a orange solid (8 g, 31%); (ES, m/z): [M+H]⁺ 455; ¹H NMR (300 MHz,CDCl₃): δ 7.97 (d, J=6.0 Hz, 1H), 7.05-7.09 (m, 3H), 6.87-6.96 (m, 3H),6.18 (s, 1H), 1.26-1.33 (m, 3H), 1.13 (s, 18H).

Step 9. Formation of 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenol

To a solution of4-nitro-3-(trifluoromethyl)-N-(4-[[tris(propan-2-yl)silyl]oxy]phenyl)aniline(3 g, 6.6 mmol) in tetrahydrofuran (60 ml) was added TBAF (2.59 g, 9.9mmol) with stirring for 1 hour at room temperature. The reaction mixturewas diluted with water (100 ml) and extracted with dichloromethane (3×50ml), dried over anhydrous magnesium sulfate, and concentrated undervacuum to give a residue, which was applied onto a silica gel column andeluted with 30% ethyl acetate in petroleum ether to afford4-[[4-nitro-3-(trifluoromethyl) phenyl]amino]phenol as a orange solid(1.5 g, 76%); (ES, m/z): [M+H]⁺ 299; ¹H NMR (300 MHz, DMSO-d6): δ 9.53(s, 1H), 9.28 (s, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.18 (d, J=2.4 Hz, 1H),7.07 (d, J=8.7 Hz, 2H), 7.01-7.05 (m, 1H), 6.81 (d, J=8.7 Hz, 2H).

Step 10. Formation of1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)ethan-1-one (#68)

To a solution of1-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]-4-(2-chloroethyl)piperazine (200 mg, 0.61 mmol) in acetonitrile (5 ml) was addedpotassium carbonate (139 mg, 1.01 mmol, 1.6 eq.),4-[4-nitro-3-(trifluoromethyl)phenyl]aminophenol (200 mg, 0.67 mmol, 1.1eq.) and KI (56 mg, 0.34 mmol, 0.6 eq.) with stirring for 3 hours at 70°C. (oil bath). The reaction mixture was concentrated under vacuum togive a residue, which was purified by silica gel column chromatographyusing 2% dichloromethane in methanol to afford1-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)ethan-1-oneas a orange solid (150.3 mg, 36%); (ES, m/z): [M+H]⁺ 591.15; ¹H NMR (300MHz, CDCl₃): δ 7.98 (d, J=9.0 Hz, 1H), 6.91-7.11 (m, 4H), 7.08 (d, J=8.7Hz, 1H), 7.01 (d, J=8.7 Hz, 2H), 6.92 (dd, J=2.7, 9.0 Hz, 1H), 6.69 (d,J=8.4 Hz, 1H), 6.32 (s, 1H), 4.93-5.09 (m, 1H), 4.75 (s, 2H), 3.65-3.78(m, 4H), 3.28 (dd, J=9.3, 15.9 Hz, 1H), 2.97 (dd, J=8.1, 15.6 Hz, 1H),2.79 (dd, J=7.5, 13.5 Hz, 1H), 2.60-2.75 (m, 5H).

Compound 82:4-[[4-(3-[4-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]-piperazin-1-yl]-2-oxopropoxy)cyclohexyl]amino]-2-(trifluoromethyl)benzonitrile

(ES, m/z): [M+H]⁺ 577.20; ¹H NMR (300 MHz, CDCl₃): δ 7.55 (d, J=8.7 Hz,1H), 7.13 (s, 1H), 7.07 (d, J=8.7 Hz, 1H), 6.81 (s, 1H), 6.64-6.71 (m,2H), 5.03 (br s, 1H), 4.34-4.36 (m, 1H), 4.19 (s, 2H), 3.60-3.80 (m,3H), 3.32-3.43 (m, 3H), 2.81-3.07 (m, 2H), 2.62-2.83 (m, 4H), 2.12-2.15(m, 4H), 1.65-1.79 (m, 2H), 1.26-1.48 (m, 4H).

Compound 280:4-[(4-{2-[4-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexyl)-methyl-amino]-2-trifluoromethyl-benzonitrile

(ES, m/z): [M+H]⁺ 575; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.45 (m, 2H), 1.60(m, 2H), 1.83 (d, J=12.5 Hz, 2H), 2.24 (d, J=12.0 Hz, 2H), 2.49-2.68 (m,5H), 2.73-2.81 (m, 1H), 2.86 (s, 3H), 2.99 (d, J=8.0 Hz, 1H), 3.17-3.31(m, 1H), 3.39 (s, 1H), 3.52-3.79 (m, 5H), 4.20 (s, 2H), 4.83-5.11 (m,1H), 6.68 (dd, J=8.7, 4.2 Hz, 1H), 6.73-6.83 (m, 2H), 6.84-6.90 (m, 1H),6.95 (d, J=2.3 Hz, 1H), 7.58 (d, J=8.9 Hz, 1H).

Compound 81:2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-2,3-dihydro-benzofuran-2-carbonyl)-piperazin-1-yl]-ethanone

(ES, m/z): [M+H]⁺ 645.25; ¹H NMR (300 MHz, CDCl₃): δ 8.03 (d, J=8.4 Hz,1H), 7.48 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 6.83-6.91 (m, 2H), 6.64 (dd,J=9.0, 2.7 Hz, 1H), 5.45-5.55 (m, 1H), 4.24 (s, 2H), 3.82-4.00 (m, 4H),3.30-3.75 (m, 8H), 2.14 (d, J=6.3 Hz, 4H), 1.40-1.60 (m, 2H), 1.25-1.40(m, 2H).

Compound 85:4-(4-{2-[4-(5-chloro-2,3-dihydro-benzofuran-2-carbonyl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(ES, m/z): [M+H]⁺ 591.30; ¹H NMR (300 MHz, CDCl₃): δ 7.54 (d, J=8.7 Hz,1H), 7.18 (s, 1H), 7.08 (dd, J=8.4, 2.1 Hz, 1H), 6.82 (d, J=1.8 Hz, 1H),6.62-6.74 (t, J=9.0 Hz, 2H), 5.36-5.45 (m, 1H), 4.23 (s, 2H), 3.85-3.95(m, 4H), 3.25-3.75 (m, 8H), 2.13 (d, J=10.2 Hz, 4H), 1.40-1.55 (m, 2H),1.20-1.35 (m, 2H).

Compound 86:4-(4-{2-[4-(5-fluoro-2,3-dihydro-benzofuran-2-carbonyl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(ES, m/z): [M+H]⁺ 575.20; ¹H NMR (400 MHz, CDCl₃): δ 7.57 (d, J=8.8 Hz,1H), 6.94 (d, J=6.4 Hz, 1H), 6.81-6.85 (m, 2H), 6.66-6.71 (m, 2H),5.41-5.46 (m, 1H), 4.31 (d, J 7.2 Hz, 1H), 4.25 (s, 2H), 3.85-3.94 (m,4H), 3.29-3.77 (m, 8H), 2.15-2.17 (m, 4H), 1.45-1.52 (m, 2H), 1.21-1.33(m, 2H).

Compound 87:2-[4-(4-cyano-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-2,3-dihydro-benzofuran-2-carbonyl)-piperazin-1-yl]-ethanone

(ES, m/z): [M+H]⁺ 625.40; ¹H NMR (300 MHz, CDCl₃): δ 7.54 (d, J=8.4 Hz,1H), 7.48 (s, 1H), 7.42 (d, J=8.4 Hz, 1H), 6.80-6.90 (m, 2H), 6.67 (d,J=8.7 Hz, 1H), 5.45-5.55 (m, 1H), 4.23 (s, 2H), 3.80-4.00 (m, 4H),3.30-3.70 (m, 8H), 2.14 (d, J=10.8 Hz, 4H), 1.40-1.55 (m, 2H), 1.20-1.35(m, 2H).

Compound 172:N-(7-fluoronaphthalen-2-yl)-N-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexan-1-e)oxy]ethyl]ethanediamide

(ES, m/z): [M+H]⁺ 561.00; ¹H NMR (300 MHz, CDCl₃): δ 9.41 (s, 1H), 8.34(s, 1H), 8.01 (d, J=9.0 Hz, 1H), 7.78-7.90 (m, 3H), 7.58 (m, 1H), 7.42(dd, J=2.4 Hz, 9.6 Hz, 1H), 7.31 (m, 1H), 6.84 (d, J=2.4 Hz, 1H), 6.62(dd, J=2.7 Hz, 9.0 Hz, 1H), 3.59-3.65 (m, 4H), 3.33-3.41 (m, 2H),2.11-2.18 (m, 4H), 1.41-1.53 (m, 2H), 1.24-1.35 (m, 2H).

Compound 173: N-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]-N-6-(trifluoromethyl)naphthalen-2-yl]ethanediamide

(ES, m/z): [M+H]+ 613.15; 1H NMR (400 MHz, CDCl₃): δ 9.47 (s, 1H), 8.42(s, 1H), 8.12 (s, 1H), 8.02 (d, J=8.8 Hz, 1H), 7.96-7.89 (m, 3H),7.69-7.65 (m, 2H), 6.85 (s, 1H), 6.64 (d, J=8.0 Hz, 1H), 3.66-3.58 (m,4H), 3.46-3.32 (m, 2H), 2.20-2.10 (m, 4H), 1.51-1.43 (m, 2H), 1.34-1.25(m, 2H).

Compound 174:N-(6-chloronaphthalen-2-yl)-N-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]ethanediamide

(ES, m/z): [M−H]⁻ 577.30; ¹H NMR (300 MHz, CDCl₃): δ 9.41 (s, 1H), 8.33(d, J=1.5 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 7.92-7.75 (m, 4H), 7.62 (dd,J=2.1 Hz, 8.7 Hz, 1H), 7.46 (dd, J=2.1 Hz, 8.7 Hz, 1H), 6.86 (s, 1H),6.65 (d, J=8.4 Hz, 1H), 3.66-3.56 (m, 4H), 3.45-3.35 (m, 2H), 2.18 (m,4H), 1.52-1.42 (m, 2H), 1.35-1.22 (m, 2H).

Example 23 Preparation of Compound 238

Step 1. Formation of ethyl 2-oxo-2-(quinolin-2-ylamino)acetate

To a mixture of quinolin-2-amine (200 mg, 1.4 mmol) and triethylamine(210 mg, 2.1 mmol) in dichloromethane (10 mL) was added dropwise ethyl2-chloro-2-oxoacetate (227 mg, 1.67 mmol). After stirring for 1 hour atroom temperature, the reaction was quenched with water (50 mL) andextracted with ethyl acetate (3×50 mL). The combined organic layers weredried over anhydrous sodium sulfate, filtered, and concentrated undervacuum to give a residue, which was purified by silica gel columnchromatography using 1% ethyl acetate in petroleum ether to afford ethyl2-oxo-2-(quinolin-2-ylamino)acetate as yellow solid (210 mg, 62%). (ES,m/z): [M+H]⁺ 245.1; ¹H NMR (400 MHz, CDCl₃): δ 9.65 (br s, 1H), 8.44 (d,J=8.8 Hz, 1H), 8.24 (d, J=8.8 Hz, 1H), 7.90 (d, J=8.4 Hz, 1H), 7.82 (d,J=8.0 Hz, 1H), 7.74-7.69 (m, 1H), 7.53-7.49 (m, 1H), 4.46 (q, J=7.2 Hz,2H), 1.46 (t, J=7.2 Hz, 3H).

Step 2. Formation of N¹-(2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethyl)-N²-(quinolin-2-yl)oxalamide (#238)

The mixture of ethyl 2-oxo-2-(quinolin-2-ylamino)acetate (56 mg, 0.23mmol) andN-(-4-(2-aminoethoxy)cyclohexyl)-4-nitro-3-(trifluoromethyl)benzenamine(80 mg, 0.23 mmol) in tetrahydrofuran (2 mL) was stirred overnight atroom temperature and then concentrated under vacuum to give a residue,which was purified by HPLC to affordN¹-(2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethyl)-N²-(quinolin-2-yl)oxalamide as a yellow solid (58.8mg, 46%). (ES, m/z): [M+H]⁺ 546.10; ¹H NMR (400 MHz, CDCl₃): δ 10.11 (brs, 1H), 8.41 (d, J=8.8 Hz, 1H), 8.26 (d, J=8.8 Hz, 1H), 8.01 (d, J=8.8Hz, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.82 (d, J=7.6 Hz, 2H), 7.73 (t, J=7.2Hz, 1H), 7.52 (t, J=7.2 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.65 (dd,J=8.8, 2.4 Hz, 1H), 4.48 (d, J=7.2 Hz, 1H), 3.68-3.58 (m, 4H), 3.42-3.36(m, 2H), 2.19-2.10 (m, 4H), 1.48-1.38 (m, 2H), 1.34-1.24 (m, 2H).

Compound 239:N¹-(6-fluoroquinolin-2-yl)-N²-(2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethyl)oxalamide

(ES, m/z): [M+H]⁺ 564.10; ¹H NMR (300 MHz, CDCl₃): δ 10.05 (s, 1H), 8.44(d, J=9.0 Hz, 1H), 8.20 (d, J=9.0 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H),7.95-7.91 (m, 1H), 7.83 (m, 1H), 7.53-7.43 (m, 2H), 6.85 (d, J=2.4 Hz,1H), 6.66 (dd, J=2.7, 9.0, 1H), 4.47 (br s, 1H), 3.68-3.59 (m, 4H),3.41-3.33 (m, 2H), 2.18-2.10 (m, 4H), 1.53-1.40 (m, 2H), 1.37-1.23 (m,2H).

Compound 240:N¹-(2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethyl)-N²-(6-(trifluoromethyl)quinolin-2-yl)oxalamide

(ES, m/z): [M+H]⁺ 614.2; ¹H NMR (300 MHz, CDCl₃): δ 10.19 (br s, 1H),8.54 (d, J=9.0 Hz, 1H), 8.34 (d, J=9.0 Hz, 1H), 8.14 (s, 1H), 8.06-8.00(m, 2H), 7.91 (dd, J=1.8, 9.0 Hz, 1H), 7.82 (m, 1H), 6.85 (d, J=2.4 Hz,1H), 6.63 (dd, J=9.0, 2.4 Hz, 1H), 3.66-3.60 (m, 4H), 3.45-3.33 (m, 2H),2.18-2.11 (m, 4H), 1.54-1.35 (m, 2H), 1.32-1.23 (m, 2H).

Compound 241:N¹-(6-chloroquinolin-2-yl)-N²-(2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethyl)oxalamide

(ES, m/z): [M+H]⁺ 580.10; ¹H NMR (300 MHz, CDCl₃): δ 10.02 (s, 1H), 8.44(d, J=9.0 Hz, 1H), 8.16 (d, J=9.0 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H),7.89-7.80 (m, 3H), 7.65 (dd, J=9.3, 2.4 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H),6.63 (dd, J=9.0, 2.4 Hz, 1H), 4.47 (br s, 1H), 3.66-3.59 (m, 4H),3.41-3.33 (m, 2H), 2.18-2.10 (m, 4H), 1.53-1.40 (m, 2H), 1.37-1.23 (m,2H).

Compound 242:N-(6-fluoroquinolin-2-yl)-N-methyl-N-2-[[-4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethyl)ethanediamide

(ES, m/z): [M+H]⁺ 578.05; ¹H NMR (300 MHz, CDCl₃): δ 8.21 (d, J=8.7 Hz,1H), 8.04-7.97 (m, 2H), 7.51-7.40 (m, 4H), 6.85 (d, J=2.1 Hz, 1H), 6.66(dd, J=2.4, 9.0 Hz, 1H), 3.55 (overlapping s and m, 5H), 3.42-3.32(overlapping m, 4H), 2.17-2.07 (m, 4H), 1.50-1.42 (m, 2H), 1.38-1.23 (m,2H).

Example 24 Compounds 263, 264, & 265 Formation of1-[4-(6-fluoro-naphthalen-2-yl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-henylamino)-cyclohexyloxy]-ethanethione(#263)

The amide (9 mg) was placed into a conical vial with a stir bar.Lawesson's reagent (1.5 eq.) and ˜0.5 ml of toluene were added, and thecontents were then heated at 95° C. The solid did not completelydissolve and the mixture was heated overnight. After ˜16 hours, dilutedthe contents with EtOAc and then stirred vigorously with water.Separated, dried the EtOAc layer over Na₂SO₄, filtered, andconcentrated. Chromatographed the crude material on silica gel usingMethanol/dichloromethane to elute. The product containing fractions werecombined and concentrated under vacuum to afford a yellow solid. (ES,m/z) [M+H]⁺ 593.21; ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J=8.8 Hz, 1H),7.70 (m, 2H), 7.38 (dd, J=9.2, 2.4 Hz, 1H), 7.30 (dd, J=9.2, 2.4 Hz,1H), 7.22 (dt, J=8.8, 2.8 Hz, 1H), 7.14 (d, J=2.4 Hz, 1H), 6.83 (d,J=2.8 Hz, 1H), 6.62 (dd, J=9.2, 2.4 Hz, 1H), 4.66 (s, 2H), 4.44 (m, 3H),4.12 (m, 2H), 3.60 (m, 1H), 3.38 (m, 5H), 2.15 (m, 4H), 1.45 (m, 2H),1.30 (m, 2H).

Compound 264:1-[4-(6-fluoro-quinolin-2-yl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoro-methyl-phenylamino)-cyclohexyloxy]-ethanethione

(ES, m/z) [M+H]⁺ 594.21; ¹H NMR (400 MHz, CDCl₃): δ 8.00 (d, J=9.2 Hz,1H), 7.71 (dd, J=9.2, 5.3 Hz, 1H), 7.26-7.30 (m, 1H), 7.03 (d, J=9.2 Hz,1H), 6.83 (d, J=2.5 Hz, 1H), 6.62 (dd, J=9.1, 2.6 Hz, 1H), 4.66 (s, 2H),4.37-4.44 (m, 3H), 4.06-4.10 (m, 2H), 3.84-3.91 (m, 4H), 3.56-3.64 (m,1H), 3.32-3.43 (m, 1H), 2.08-2.21 (m, 4H), 1.40-1.51 (m, 2H), 1.26-1.36(m, 4H).

Compound 265:1-[4-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanethione

(ES, m/z) [M+H]⁺ 599.22; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J=9.0 Hz,1H), 6.87 (dd, J=8.0, 2.5 Hz, 1H), 6.84 (d, J=2.7 Hz, 1H), 6.79 (td,J=8.9, 2.7 Hz, 1H), 6.68 (dd, J 8.6, 4.1 Hz, 1H), 6.62 (dd, J=9.1, 2.6Hz, 1H), 4.95-5.03 (m, 1H), 4.60 (s, 2H), 4.44 (d, J 7.6 Hz, 1H),4.23-4.35 (m, 2H), 3.93 (t, J=5.1 Hz, 2H), 3.57 (tt, J=10.1, 3.8 Hz,1H), 3.32-3.42 (m, 1H), 3.27 (dd, J=15.7, 9.1 Hz, 1H), 2.97 (dd, J=15.9,7.9 Hz, 1H), 2.80 (dd, J 13.6, 7.7 Hz, 1H), 2.59-2.76 (m, 5H), 2.08-2.18(m, 4H), 1.36-1.49 (m, 2H), 1.27-1.36 (m, 2H).

4-[(1-[4-[4-(naphthalen-2-yl)piperazin-1-yl]butanoyl]piperidin-4-yl)amino]-2-(trifluoromethyl)benzonitrile (#15)

(ES, m/z): [M+H]⁺ 550.40; ¹H NMR (400 MHz, DMSO-d6): δ 7.65-7.81 (m,4H), 7.30-7.46 (m, 2H), 7.14-7.29 (m, 3H), 7.06 (s, 1H), 6.90 (d, J=8.4Hz, 1H), 4.25 (d, J=13.2 Hz, 1H), 3.85 (d, J=13.6 Hz, 1H), 3.63-3.73 (m,1H), 3.11-3.25 (m, 5H), 2.75-2.90 (t, J=11.2 Hz, 1H), 2.52-2.62 (m, 4H),2.27-2.42 (m, 4H), 1.82-1.99 (t, J=16.4 Hz, 2H), 1.65-1.80 (m, 2H),1.15-1.40 (m, 2H).

Compound 18:4-[(1-[4-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]butanoyl]-piperidin-4-yl)amino]-2-(trifluoromethyl)benzonitrile

(ES, m/z): [M+H]⁺ 568.3; ¹H NMR (300 MHz, CDCl₃): δ 7.63-7.74 (m, 1H),7.53 (d, J=8.1 Hz, 1H), 7.35-7.39 (m, 1H), 7.19-7.30 (m, 2H), 6.85 (d,J=2.1 Hz, 1H), 6.69-6.72 (dd, J=2.1, 10.5 Hz, 1H), 4.69 (d, J=7.5 Hz,1H), 4.53-4.58 (m, 1H), 3.87-3.92 (m, 1H), 3.45-3.61 (m, 4H), 3.09-3.28(m, 4H), 2.70-2.88 (m, 3H), 2.01-2.20 (m, 4H), 1.75-1.85 (m, 1H).

Compound 21:4-[(1-[4-[4-(naphthalen-1-yl)piperazin-1-yl]butanoyl]piperidin-4-yl)amino]-2-(trifluoromethyl)benzonitrile

(ES, m/z): [M+H]⁺ 550; ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J=6.3 Hz,1H), 7.85 (m, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.54 (m, 3H), 7.43 (t, J=8.1Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.86 (d, J=2.1 Hz, 1H), 6.70 (dd,J=6.3, 8.4 Hz, 1H), 4.52 (d, J=13.5 Hz, 1H), 3.85 (m, 3H), 3.60 (m, 1H),3.31 (m, 4H), 3.22 (m, 4H), 2.88 (m, 1H), 2.60 (m, 2H), 2.20 (m, 4H),1.48 (m, 4H).

Compound 94:4-[(1-[4-[4-(quinolin-2-yl)piperazin-1-yl]butanoyl]piperidin-4-yl)amino]-2-(trifluoromethyl)benzonitrile

(ES, m/z): [M+H]⁺ 551.15; ¹H NMR (300 MHz, CDCl₃): δ 7.88-7.95 (d, J=9.0Hz, 1H), 7.69 (d, J=8.4 Hz, 1H), 7.52-7.62 (m, 3H), 7.23 (d, J=7.2 Hz,1H), 6.97 (d, J=9.0 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.69 (dd, J=2.1,5.7 Hz, 1H), 4.55 (d, J=14.4 Hz, 1H), 4.47 (d, J=7.8 Hz, 1H), 3.93 (d,J=14.4 Hz, 1H), 3.77-3.80 (t, J=4.8 Hz, 4H), 3.58-3.61 (m, 1H),3.18-3.26 (t, J=11.7 Hz, 1H), 2.82-2.90 (t, J=11.7 Hz, 1H), 2.65 (t,J=4.5 Hz, 4H), 2.44-2.54 (m, 4H), 2.06-2.15 (m, 2H), 1.88-1.98 (m, 2H),1.43-1.47 (m, 2H).

Compound 95:2-(trifluoromethyl)-4-[[1-(4-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]butanoyl)piperidin-4-yl]amino]benzonitrile

(ES, m/z) [M+H]⁺ 619.36; ¹H NMR (300 MHz, CDCl3): δ 7.95 (d, J=8.7 Hz,1H), 7.89 (s or fine coupling, 1H), 7.72 (m, 2H), 7.56 (d, J=8.7 Hz,1H), 7.03 (d, J=9.3 Hz, 1H), 6.85 (d, J=2.1 Hz, 1H), 6.78 (dd, J=2.1,8.4 Hz, 1H), 4.55-4.60 (m, 1H), 4.39-4.41 (m, 1H), 3.85-3.97 (m, 5H),3.56-3.70 (m, 1H), 3.23 (t, J=12.0 Hz, 1H), 2.86 (t, J=11.4 Hz, 1H),2.44-2.76 (m, 7H), 2.08-2.16 (m, 2H), 1.96-2.11 (m, 2H), 1.43-1.47 (m,2H).

4-[(1-[4-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]butanoyl]piperidin-4-yl)amino]-2-(trifluoromethyl)benzonitrile (#96)

(ES, m/z): [M+H]⁺ 585.20; ¹H NMR (300 MHz, CDCl₃): δ 7.80 (d, J=9.3 Hz,1H), 7.53-7.65 (m, 3H), 7.44 (dd, J=2.1 Hz, 9.0 Hz, 1H), 7.00 (d, J=9.3Hz, 1H), 6.85 (s, 1H), 6.66 (dd, J=2.1 Hz, 8.4 Hz, 1H), 4.57 (d, J=13.5Hz, 1H), 4.42 (d, J=7.5 Hz, 1H), 3.96 (d, J=13.8 Hz, 1H), 3.70-3.85 (brs, 4H), 3.52-3.65 (m, 1H), 3.18 (t, J=11.7 Hz, 1H), 2.83 (t, J=12.0 Hz,1H), 2.55-2.70 (br s, 4H), 2.40-2.55 (m, 4H), 2.03-2.15 (m, 2H),1.86-1.96 (m, 2H), 1.35-1.45 (m, 2H).

Compound 103:4-[(1-[4-[4-(6-fluoroquinolin-2-yl)piperazin-1-yl]butanoyl]piperidin-4-yl)amino]-2-(trifluoromethyl)benzonitrile

(ES, m/z): [M+H]⁺ 569.15; ¹H NMR (300 MHz, CDCl₃): δ 7.83 (d, J=9.0 Hz,1H), 7.67 (dd, J=5.4, 9.0 Hz, 1H), 7.55 (d, J=8.7 Hz, 1H), 7.22-7.34 (m,2H), 6.99 (d, J=9.3 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H), 6.70 (dd, J=2.7,8.4 Hz, 1H), 4.57 (br d, J=14.1 Hz, 1H), 4.45 (d, J=7.8 Hz, 1H), 3.95(br d, J=12.9 Hz, 1H), 3.77 (br s, 4H), 3.55-3.64 (m, 1H), 3.22 (dd,J=11.7, 12.0 Hz, 1H), 2.87 (dd, J=11.1, 11.4 Hz, 1H), 2.67 (br s, 4H),2.44-2.54 (m, 4H), 2.11-2.15 (m, 2H), 1.92-1.96 (m, 2H), 1.41-1.47 (m,2H).

Compound 104:4-[(1-[4-[4-(4-methylquinolin-2-yl)piperazin-1-yl]butanoyl]piperidin-4-yl)amino]-2-(trifluoromethyl)benzonitrile

(ES, m/z): [M+H]⁺ 565.10. ¹H NMR (300 MHz, CDCl₃): δ 7.79 (d, J=8.1 Hz,1H), 7.72 (d, J=8.4 Hz, 1H), 7.57 (m, 2H), 7.25-7.30 (m, 1H), 6.85 (m,2H), 6.70 (dd, J=2.1, 87 Hz, 1H), 4.57 (br d, J=13.8 Hz, 1H), 4.85 (d,J=6.3 Hz, 1H), 3.95 (br d, J=13.2 Hz, 1H), 3.83 (br s, 4H), 3.59-3.62(m, 1H), 3.19-3.26 (dd, J=11.4, 12.0 Hz, 1H), 2.86 (dd, J=11.1, 12.0 Hz,1H), 2.70 (br s, 4H), 2.40-2.61 (m, 6H), 2.06-2.15 (m, 2H), 1.94-2.01(m, 2H), 1.35-1.58 (m, 2H).

ethyl 4-[4-(6-fluoro-4-methylquinolin-2-yl)piperazin-1-yl]butanoate(#105)

(ES, m/z): [M+H]⁺ 583.00; ¹H NMR (300 MHz, CDCl₃): δ 7.70 (dd, J=5.4 Hz,9.3 Hz, 1H), 7.56 (d, J=8.7 Hz, 1H), 7.41 (dd, J=2.7 Hz, 9.9 Hz, 1H),7.32 (dd, J=2.7 Hz, 8.7 Hz, 1H), 6.86 (s, 2H), 6.72 (dd, J=2.1 Hz, 8.7Hz, 1H), 4.59-4.49 (overlapping m, 2H), 3.94 (d, J=13.8 Hz, 1H), 3.76(br s, 4H), 3.65-3.55 (m, 1H), 3.27 (d, J=11.1, 12.0 Hz, 1H), 2.91 (dd,J=11.4, 11.7 Hz, 1H), 2.66 (br s, 4H), 2.65-2.43 (m, 7H), 2.15 (m, 2H),2.00-1.88 (m, 2H), 1.47-1.40 (m, 2H).

Compound 343:2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-{4-[1-(5-trifluoromethyl-benzothiazol-2-yl)-ethyl]-piperazin-1-yl}-ethanone

(CI, m/z): [M+H]⁺ 660; ¹H NMR (400 MHz, CDCl₃) δ 1.24-1.36 (m, 2H),1.37-1.52 (m, 2H), 1.59 (br s, 3H), 2.14 (d, J=9.2 Hz, 4H), 2.51-2.82(m, 4H), 3.28-3.48 (m, 3H), 3.55-3.80 (m, 4H), 4.20 (s, 2H), 4.44 (d,J=7.4 Hz, 1H), 6.63 (dd, J=9.0, 2.6 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H),7.62 (d, J=8.1 Hz, 1H), 8.00 (dd, J=12.7, 8.6 Hz, 2H), 8.20-8.28 (m,1H).

Example 25 Preparation of Compound 365

Steps 1-2

The formation of 2-chloromethyl-5-trifluoromethyl-benzothiazolehydrochloride was performed in a manner analogous to that described forcompound 235 with a difference being the use of BOC-piperazine in lieuof piperazine.

Steps 3-4

The formation of2-((2S,5R)-2,5-dimethyl-piperazin-1-ylmethyl)-5-trifluoromethyl-benzothiazolehydrochloride was performed in a manner analogous to that described forcompound 285.

Step 5. Formation of1-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone(#365)

To a solution of[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-acetic acid(172 mg, 0.476 mmol, 2 eq.) in DMF (5 ml) was added EDAC hydrochloride(68 mg, 0.36 mmol, 1.5 eq.), HOBt (55 mg, 0.36 mmol, 1.5 eq.) and4-methylmorpholine (0.13 ml, 1.2 mmol, 5 eq.). The resulting solutionwas stirred for 30 min then2-((2S,5R)-2,5-dimethyl-piperazin-1-ylmethyl)-5-trifluoromethyl-benzothiazolehydrochloride (87 mg, 0.24 mmol, 1 eq.) was added. The solution wasstirred overnight at room temperature and diluted with EtOAc (25 ml) andwashed with water (25 ml), saturated aqueous lithium chloride (25 ml)and brine (25 ml), dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to give a residue, which was applied onto asilica gel column with Heptanes-EtOAc to afford1-[(2R,5S)-2,5-dimethyl-4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanoneas a yellow solid (86.1 mg, 53.7%). (CI, m/z): [M+H]⁺ 674; ¹H NMR (400MHz, CDCl₃) δ 1.02-1.53 (m, 10H), 2.18 (br s, 4H), 2.47 (d, J=11.7 Hz,1H), 2.99 (d, J=8.8 Hz, 1H), 3.23 (br s, 1H), 3.31-3.53 (m, 2H),3.85-4.13 (m, 4H), 4.20 (br s, 3H), 4.46 (d, J=7.6 Hz, 1H), 6.64 (dd,J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 7.63 (d, J=8.3 Hz, 1H), 8.01(t, J=8.3 Hz, 2H), 8.21 (s, 1H).

Compound 370:1-[(2R,5S)-4-(5-fluoro-benzothiazol-2-ylmethyl)-2,5-dimethyl-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 624; ¹H NMR (400 MHz, CDCl₃) δ 0.94-1.83 (m, 10H),2.16 (d, J=10.0 Hz, 4H), 2.53 (br s, 1H), 2.99 (d, J=8.6 Hz, 1H),3.13-3.51 (m, 4H), 3.54-4.39 (m, 6H), 4.51 (d, J=7.2 Hz, 1H), 6.64 (dd,J=9.1, 2.4 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 7.17 (td, J=8.8, 2.2 Hz,1H), 7.64 (dd, J=9.4, 2.2 Hz, 1H), 7.81 (dd, J=8.7, 5.1 Hz, 1H), 8.02(d, J=9.0 Hz, 1H).

Compound 371:1-[(3S,5R)-4-(5-fluoro-benzothiazol-2-ylmethyl)-2,5-dimethyl-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 624; ¹H NMR (400 MHz, CDCl₃) δ 1.19 (d, J=4.6 Hz, 6H),1.25-1.36 (m, 2H), 1.37-1.53 (m, 2H), 2.05-2.24 (m, 4H), 2.45-2.63 (m,1H), 2.77 (d, J=3.7 Hz, 2H), 2.87-3.07 (m, 1H), 3.23-3.52 (m, 2H), 3.83(d, J=13.0 Hz, 1H), 4.13-4.29 (m, 4H), 4.41 (d, J=13.0 Hz, 1H), 4.48 (d,J=7.7 Hz, 1H), 6.63 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H),7.13 (td, J=8.8, 2.4 Hz, 1H), 7.63 (dd, J=9.5, 2.4 Hz, 1H), 7.78 (dd, J8.8, 5.2 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H).

Compound 315:4-(4-{2-[4-(3,5-dichloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(ES, m/z): [M+H]⁺ 609; ¹H NMR (400 MHz, CDCl₃) δ 1.16-1.27 (m, 2H),1.36-1.52 (m, 2H), 2.10 (d, J=9.0 Hz, 4H), 2.59 (br s, 4H), 3.19-3.46(m, 2H), 3.51-3.70 (m, 4H), 3.81 (s, 2H), 4.14-4.21 (m, 2H), 4.28 (d,J=7.6 Hz, 1H), 6.65 (dd, J=8.6, 2.2 Hz, 1H), 6.81 (d, J=2.1 Hz, 1H),7.31 (dd, J=8.8, 2.1 Hz, 1H), 7.36-7.44 (m, 1H), 7.47-7.60 (m, 2H).

Compound 316:1-[4-(3,5-dichloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(ES, m/z): [M+H]⁺ 629; ¹H NMR (400 MHz, CDCl₃) δ 1.17-1.28 (m, 2H),1.37-1.51 (m, 2H), 2.12 (d, J=11.0 Hz, 4H), 2.59 (br s, 4H), 3.29-3.45(m, 2H), 3.52-3.71 (m, 4H), 3.81 (s, 2H), 4.18 (s, 2H), 4.41 (d, J=7.5Hz, 1H), 6.63 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 7.31 (dd,J=8.8, 2.1 Hz, 1H), 7.37-7.46 (m, 1H), 7.54 (d, J=2.0 Hz, 1H), 8.02 (d,J=9.0 Hz, 1H).

Compound 267:1-[4-(6-bromo-1-fluoro-naphthalen-2-yl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 653.1; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J=9.0 Hz,1H), 7.90 (m, 1H), 7.89 (d, J=8.8 Hz, 1H), 7.56 (dd, J=8.9, 1.9 Hz, 1H),7.50 (d, J=9.0 Hz, 1H), 7.23 (dd, J=8.8, 8.4 Hz, 1H), 6.84 (d, J=2.3 Hz,1H), 6.63 (dd, J=8.9, 2.6 Hz, 1H), 4.43 (d, J=7.7 Hz, 1H), 4.26 (s, 2H),3.70-3.90 (m, 4H), 3.31-3.54 (m, 2H), 3.24 (m, 4H), 2.21 (m, 4H), 1.45(m, 2H), 1.28 (m, 2H).

Compound 289:1-[4-(1,6-difluoro-naphthalen-2-yl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 593; ¹H NMR (400 MHz, CDCl₃): δ 1.26-1.39 (m, 2H),1.41-1.55 (m, 2H), 2.17 (d, J=10.4 Hz, 4H), 3.22 (br s, 4H), 3.31-3.58(m, 2H), 3.67-3.95 (m, 4H), 4.27 (s, 2H), 4.47 (d, J=7.7 Hz, 1H), 6.64(dd, J=9.0, 2.5 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 7.29-7.33 (m, 2H), 7.41(d, J=9.6 Hz, 1H), 7.54 (d, J=8.9 Hz, 1H), 7.88-8.10 (m, 2H).

Compound 290:4-(4-{2-[4-(1,6-difluoro-naphthalen-2-yl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(CI, m/z): [M+H]⁺ 573; ¹H NMR (400 MHz, CDCl₃): δ 1.28-1.37 (m, 2H),1.48 (br s, 2H), 2.08-2.28 (m, 4H), 3.22 (br s, 4H), 3.29-3.55 (m, 2H),3.64-3.96 (m, 4H), 4.27 (s, 3H), 6.53-6.70 (m, 1H), 6.82 (d, J=2.0 Hz,1H), 7.28 (m, 2H), 7.36-7.45 (m, 1H), 7.54 (t, J=8.0 Hz, 2H), 7.95-8.10(m, 1H).

Compound 300:1-[4-(5-chloro-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(ES, m/z): [M+H]⁺ 609; ¹H NMR (400 MHz, CDCl₃): δ 1.11-1.25 (m, 2H),1.33-1.45 (m, 2H), 1.52 (s, 3H), 2.08 (m, 4H), 2.40-2.71 (m, 4H),3.24-3.43 (m, 2H), 3.46-3.74 (m, 4H), 3.90 (q, J=7.0 Hz, 1H), 4.14 (brs, 2H), 4.48 (d, J=7.6 Hz, 1H), 6.49 (s, 1H), 6.61 (dd, J=9.1, 2.5 Hz,1H), 6.84 (d, J=2.3 Hz, 1H), 7.20 (dd, J=8.7, 2.10 Hz, 1H), 7.38 (s,1H), 7.50 (s, 1H), 8.02 (d, J=8.9 Hz, 1H).

Example 26 Preparation of Compound 327

Formation of2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(7-trifluoromethyl-quinolin-3-ylmethyl)-piperazin-1-yl]-ethanone

To a solution of 3-chloromethyl-7-trifluoromethyl-quinoline (140 mg,0.57 mmol, 1.1 eq.) in DMF (10 ml) was added potassium carbonate (345mg, 2.5 mmol, 5 eq.) then2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanonehydrochloride (233 mg, 0.5 mmol, 1 eq.) was added. The solution wasstirred overnight at 70° C. and diluted with EtOAc (25 ml) and washedwith water (25 ml), saturated aqueous lithium chloride (25 ml) and brine(25 ml), dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to give a residue, which was applied onto a silica gelcolumn and eluted with methanol in dichloromethane. The semi-purifiedmaterial was further purified by HPLC to afford2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(7-trifluoromethyl-quinolin-3-ylmethyl)-piperazin-1-yl]-ethanoneas a yellow solid (111.2 mg, 30%). (CI, m/z): [M+H]⁺ 640; ¹H NMR (400MHz, CDCl₃): δ 1.20-1.36 (m, 2H), 1.40-1.54 (m, 2H), 2.08-2.21 (m, 4H),2.46-2.61 (m, 4H), 3.32-3.49 (m, 2H), 3.53-3.62 (m, 2H), 3.63-3.71 (m,2H), 3.76 (s, 2H), 4.20 (s, 2H), 4.46 (d, J=7.6 Hz, 1H), 6.63 (dd,J=9.1, 2.6 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 7.75 (dd, J=8.5, 1.6 Hz, 1H)7.94 (d, J=8.5 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 8.13 (d, J=1.2 Hz, 1H),8.43 (s, 1H), 9.03 (d, J=2.1 Hz, 1H).

Compound 328:2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(7-trifluoromethyl-quinolin-2-ylmethyl)-piperazin-1-yl]-ethanone

(CI, m/z): [M+H]⁺ 640; ¹H NMR (400 MHz, CDCl₃): δ 1.28-1.35 (m, 2H),1.39-1.54 (m, 2H), 2.14 (d, J=9.3 Hz, 4H), 2.59 (t, J=5.0 Hz, 4H),3.31-3.50 (m, 2H), 3.53-3.74 (m, 4H), 3.90 (s, 2H), 4.20 (s, 2H), 4.46(d, J=7.6 Hz, 1H), 6.64 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H),7.65-7.80 (m, 2H), 7.95 (d, J=8.5 Hz, 1H), 8.02 (d, J=9.0 Hz, 1H), 8.22(d, J=8.5 Hz, 1H), 8.41 (s, 1H).

Compound 329:2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-quinolin-2-ylmethyl)-piperazin-1-yl]-ethanone

(CI, m/z): [M+H]⁺ 640; ¹H NMR (400 MHz, CDCl₃): δ 1.28-1.36 (m, 2H),1.39-1.54 (m, 2H), 2.14 (d, J=9.1 Hz, 4H), 2.58 (t, J=4.6 Hz, 4H),3.29-3.49 (m, 2H), 3.50-3.78 (m, 4H), 3.89 (s, 2H), 4.20 (s, 2H), 4.47(d, J=7.6 Hz, 1H), 6.64 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (m, 1H), 7.66-7.82(m, 2H), 7.92 (d, J=7.3 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H), 8.27 (d, J=8.5Hz, 1H), 8.50 (d, J=8.0 Hz, 1H).

Compound 232:2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(6-trifluoromethyl-naphthalen-2-yl)-piperazin-1-yl]-ethanone

(CI, m/z): [M+H]⁺ 640; ¹H NMR (400 MHz, CDCl₃) δ ppm 1.30 (d, J=12.6 Hz,2H), 1.50 (d, J=12.6 Hz, 2H), 2.17 (d, J=10.4 Hz, 4H), 3.19-3.59 (m,6H), 3.68-3.95 (m, 4H), 4.28 (s, 2H), 4.44 (d, J=7.6 Hz, 1H), 6.64 (dd,J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 7.15 (d, J=1.9 Hz, 1H), 7.35(dd, J=9.0, 2.3 Hz, 1H), 7.59 (d, J=8.7 Hz, 1H), 7.69-7.88 (m, 2H),7.94-8.09 (m, 2H).

Compound 332:2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(6-trifluoromethyl-quinolin-2-ylmethyl)-piperazin-1-yl]-ethanone

(CI, m/z): [M+H]⁺ 640; ¹H NMR (400 MHz, CDCl₃): δ 1.29-1.36 (m, 2H),1.39-1.52 (m, 2H), 2.14 (d, J=9.5 Hz, 4H), 2.58 (t, J=5.0 Hz, 4H),3.27-3.48 (m, 2H), 3.54-3.75 (m, 4H), 3.90 (s, 2H), 4.20 (s, 2H), 4.45(d, J=7.6 Hz, 1H), 6.64 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.4 Hz, 1H),7.75 (d, J=8.5 Hz, 1H), 7.90 (dd, J=8.8, 1.8 Hz, 1H), 8.02 (d, J=9.0 Hz,1H), 8.10-8.21 (m, 2H), 8.25 (d, J=8.5 Hz, 1H).

Compound 333:4-(4-{2-oxo-2-[4-(7-trifluoromethyl-quinolin-2-ylmethyl)-piperazin-1-yl]ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(CI, m/z): [M+H]⁺ 620; ¹H NMR (400 MHz, CDCl₃): δ 1.28-1.35 (m, 2H),1.37-1.51 (m, 2H), 2.13 (d, J=9.8 Hz, 4H), 2.58 (t, J=5.0 Hz, 4H),3.24-3.48 (m, 2H), 3.50-3.77 (m, 4H), 3.90 (s, 2H), 4.16 (s, 2H), 4.29(d, J=7.6 Hz, 1H), 6.66 (dd, J=8.6, 2.2 Hz, 1H), 6.81 (d, J=2.2 Hz, 1H),7.55 (d, J=8.6 Hz, 1H), 7.65-7.80 (m, 2H), 7.95 (d, J=8.5 Hz, 1H), 8.22(d, J=8.5 Hz, 1H), 8.41 (s, 1H).

Compound 334:4-(4-{2-oxo-2-[4-(6-trifluoromethyl-quinolin-2-ylmethyl)-piperazin-1-yl]-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(CI, m/z): [M+H]⁺ 620; ¹H NMR (400 MHz, CDCl₃): δ 1.28-1.36 (m, 2H),1.38-1.52 (m, 2H), 2.13 (d, J=9.7 Hz, 4H), 2.58 (t, J=4.9 Hz, 4H),3.25-3.48 (m, 2H), 3.52-3.74 (m, 4H), 3.90 (s, 2H), 4.20 (s, 2H), 4.29(d, J=7.6 Hz, 1H), 6.66 (dd, J=8.6, 2.12 Hz, 1H), 6.81 (d, J=2.0 Hz,1H), 7.55 (d, J=8.5 Hz, 1H), 7.75 (d, J=8.5 Hz, 1H), 7.90 (d, J=8.8 Hz,1H), 8.08-8.21 (m, 2H), 8.25 (d, J=8.5 Hz, 1H).

Example 27 Preparation of Compound 342

Steps 1-4

The formation of 2-bromo-5-trifluoromethyl-benzothiazole was performedin a manner analogous to that described for compound 237.

Step 5. Formation of2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperazin-1-yl]-ethanone(#342)

To a solution of 2-bromo-5-trifluoromethyl-benzothiazole (430 mg, 1.4mmol, 1 eq.) in toluene (15 ml) was added sodium tert-butoxide (546 mg,5.7 mmol, 4 eq.), BINAP (10 mg, 0.015 mmol, 0.01 eq.) and2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanonehydrochloride (1.33 g, 2.84 mmol, 2 eq.). The solution was flushed withnitrogen and evacuated three times before adding Pd₂(dba)₃-CHCl₃ (31 mg,0.03 mmol, 0.02 eq.) and flushing/evacuating a final time. The slurrywas heated to for 18 hours at 70° C. before concentrating in vacuo. Theresidue was applied onto a silica gel column and eluted withHeptanes/EtOAc to afford2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperazin-1-yl]-ethanoneas a yellow solid (662 mg, 73.8%). (CI, m/z): [M+H]⁺ 632; ¹H NMR (400MHz, CDCl₃): δ 1.29-1.38 (m, 2H), 1.41-1.56 (m, 2H), 2.16 (d, J=8.9 Hz,4H), 3.26-3.53 (m, 2H), 3.55-3.90 (m, 8H), 4.26 (s, 2H), 4.47 (d, J=7.6Hz, 1H), 6.63 (dd, J=9.1, 2.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 7.36 (d,J=8.2 Hz, 1H), 7.72 (d, J=8.2 Hz, 1H), 7.81 (s, 1H), 8.01 (d, J=9.0 Hz,1H).

4-(4-{2-oxo-2-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperazin-1-yl]-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile(#358)

(CI, m/z): [M+H]⁺ 612; ¹H NMR (400 MHz, CDCl₃): δ 1.18-1.35 (m, 2H),1.36-1.53 (m, 2H), 2.15 (d, J=10.5 Hz, 4H), 3.24-3.52 (m, 2H), 3.54-3.87(m, 8H), 4.30 (d, J=7.6 Hz, 3H), 6.66 (dd, J=8.6, 2.2 Hz, 1H), 6.81 (d,J=2.2 Hz, 1H), 7.36 (d, J=7.6 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.72 (d,J=8.2 Hz, 1H), 7.82 (s, 1H).

Compound 364:2-[4-(4-trifluoromethanesulfonyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzothiazol-2-yl)-piperazin-1-yl]-ethanone

(CI, m/z): [M+H]⁺ 651; ¹H NMR (400 MHz, CDCl₃): δ 1.28-1.39 (m, 2H),1.41-1.56 (m, 2H), 2.16 (d, J=10.7 Hz, 4H), 3.30-3.54 (m, 2H), 3.61-3.90(m, 8H), 4.26 (s, 2H), 4.45 (d, J=7.6 Hz, 1H), 6.63 (d, J=8.9 Hz, 2H),7.36 (d, J=8.2 Hz, 1H), 7.65-7.78 (m, 3H), 7.81 (s, 1H).

1-[(3S,5R)-4-(6-fluoro-naphthalen-2-ylmethyl)-3,5-dimethyl-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone(#372)

(CI, m/z): [M+H]⁺ 617; ¹H NMR (400 MHz, CDCl₃): δ 1.12 (dd, J=8.8, 5.8Hz, 6H), 1.28-1.35 (m, 2H), 1.38-1.51 (m, 2H), 2.05-2.21 (m, 4H), 2.65(d, J=9.7 Hz, 3H), 2.84-3.12 (m, 1H), 3.20-3.50 (m, 2H), 3.77 (d, J=13.0Hz, 1H), 3.96 (s, 2H), 4.15-4.25 (m, 2H), 4.33 (d, J=8.2 Hz, 1H), 4.43(d, J=7.6 Hz, 1H), 6.63 (dd, J=9.0, 2.5 Hz, 1H), 6.85 (d, J 2.3 Hz, 1H),7.17-7.27 (m, 1H), 7.43 (dd, J=9.8, 2.2 Hz, 1H), 7.50 (d, J=8.4 Hz, 1H),7.73 (d, J=8.5 Hz, 1H), 7.76-7.88 (m, 2H), 8.03 (d, J=9.0 Hz, 1H).

Compound 357:1-[(2R,5S)-4-(6-fluoro-naphthalen-2-ylmethyl)-2,5-dimethyl-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 617; ¹H NMR (400 MHz, CDCl₃): δ 0.79-0.92 (m, 2H),1.04 (br s, 2H), 1.13-1.38 (m, 6H), 1.38-1.52 (m, 3H), 2.15 (d, J=8.7Hz, 4H), 2.31 (d, J=11.8 Hz, 1H), 2.78 (d, J=8.5 Hz, 1H), 3.08 (br s,1H), 3.30-3.52 (m, 2H), 3.62 (d, J=13.4 Hz, 1H), 3.79 (d, J=13.5 Hz,1H), 3.97-4.32 (m, 2H), 4.46 (d, J=7.6 Hz, 1H), 6.64 (dd, J=9.0, 2.51Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 7.21-7.27 (m, 1H), 7.45 (dd, J=9.8, 2.3Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.65-7.86 (m, 3H), 8.02 (d, J=9.0 Hz,1H).

1-[(2R,5S)-2,5-dimethyl-4-(6-trifluoromethyl-naphthalen-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone(#373)

(ES, m/z): [M+H]⁺ 667; ¹H NMR (400 MHz, CDCl₃): δ 1.05 (br s, 3H), 1.32(m, 5H), 1.42-1.52 (m, 2H), 2.15 (d, J=7.0 Hz, 4H), 2.30 (d, J=11.7 Hz,1H), 2.80 (d, J=9.1 Hz, 1H), 3.09 (br s, 1H), 3.33-3.53 (m, 3H) 3.67 (d,J=13.7 Hz, 2H), 3.84 (d, J=13.7 Hz, 1H), 4.08-4.34 (m, 3H), 4.47 (d,J=7.6 Hz, 1H), 6.64 (dd, J=9.0, 2.5 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H),7.66 (t, J=8.2 Hz, 2H), 7.82 (s, 1H), 7.92 (s, 2H), 8.02 (d, J=9.0 Hz,1H), 8.14 (s, 1H).

Compound 374:1-[(3S,5R)-3,5-dimethyl-4-(6-trifluoromethyl-naphthalen-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(ES, m/z): [M+H]⁺ 667; ¹H NMR (400 MHz, CDCl₃): δ 1.09 (t, J=6.7 Hz,6H), 1.31 (br s, 2H), 1.39-1.52 (m, 2H), 2.13 (t, J=10.6 Hz, 4H),2.53-2.75 (m, 3H), 2.95-3.09 (m, 1H), 3.25-3.54 (m, 2H), 3.79 (d, J=12.6Hz, 1H), 3.98 (d, J=2.9 Hz, 2H), 4.15-4.26 (m, 2H), 4.35 (d, J=8.5 Hz,1H), 4.45 (d, J=7.6 Hz, 1H), 6.63 (dd, J=9.1, 2.4 Hz, 1H), 6.85 (d,J=2.2 Hz, 1H), 7.62 (dd, J=16.7, 8.2 Hz, 2H), 7.79-7.97 (m, 3H), 8.02(d, J=9.0 Hz, 1H), 8.13 (s, 1H).

Compound 381:1-[(3S,5R)-4-(6-fluoro-quinolin-2-yl)-3,5-dimethyl-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 604; ¹H NMR (400 MHz, CDCl₃): δ 1.32 (dd, J=15.7, 6.7Hz, 8H), 1.43-1.53 (m, 2H), 2.01-2.33 (m, 4H), 3.06 (dd, J=13.0, 4.2 Hz,1H), 3.27-3.58 (m, 3H), 3.93 (d, J=13.3 Hz, 1H), 4.21-4.40 (m, 2H),4.41-4.56 (m, 2H), 4.63 (br s, 1H), 4.86 (br s, 1H), 6.64 (dd, J=9.1,2.5 Hz, 1H), 6.86 (d, J=2.3 Hz, 1H), 6.95 (d, J=9.3 Hz, 1H), 7.25 (m,1H), 7.32 (td, J=8.8, 2.9 Hz, 1H), 7.68 (dd, J=9.1, 5.2 Hz, 1H), 7.89(d, J=9.2 Hz, 1H), 8.02 (d, J=9.1 Hz, 1H).

Compound 20:1-[4-(naphthalen-1-yl)piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 557; ¹H NMR (400 MHz, CDCl₃): δ 8.20 (d, J=7.5 Hz,1H); 8.01 (d, J=8.7 Hz, 1H), 7.85 (d, J=7.5 Hz, 1H), 7.61 (d, J=8.4 Hz,1H), 7.51 (m, 3H), 7.41 (dd, J 7.2, 8.4 Hz, 1H), 7.07 (d, J=7.5 Hz, 1H),6.85 (s, 1H), 6.6 (d, J=7.8 Hz, 1H), 4.50 (br s, 1H), 4.28 (s, 2H), 3.82(br m, 2H), 3.45 (br m, 3H), 3.13 (m, 4H), 2.17 (d, J=6.6 Hz, 4H), 1.51(m, 2H), 1.25 (m, 2H).

Compound 268:1-[4-(6-bromo-naphthalen-2-yl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 635.1; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J=8.8 Hz,1H), 7.88 (d, J=1.8 Hz, 1H), 7.67 (d, J=9.2 Hz, 1H), 7.57 (d, J=8.8 Hz,1H), 7.48 (dd, J=9.2, 2.0 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H), 6.84 (d,J=2.4 Hz, 1H), 6.63 (dd, J=9.1, 2.6 Hz, 1H), 4.44 (d, J=7.7 Hz, 1H),4.26 (s, 2H), 3.68-3.88 (m, 4H), 3.34-3.52 (m, 2H), 3.23-3.33 (m, 4H),2.16 (d, J=10.0 Hz, 4H), 1.47 (s, 2H), 1.20-1.37 (m, 2H).

Compound 311:2-[4-(4-nitro-3-trifluoromethyl-phenoxy)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-piperazin-1-yl]-ethanone

(CI, m/z): [M+H]⁺ 647.2; ¹H NMR (400 MHz, CDCl₃): δ 8.23 (s, 1H), 8.01(d, J=9.2 Hz, 2H), 7.62 (dd, J=8.4, 1.2 Hz, 1H), 7.22-7.31 (m, 1H,overlaps CHCl₃), 7.07 (dd, J=9.0, 2.7 Hz, 1H), 4.42-4.53 (m, 1H), 4.19(s, 2H), 4.03 (s, 2H), 3.60-3.76 (m, 4H), 3.51-3.61 (m, 1H), 2.69 (t,J=5.0 Hz, 4H), 1.99-2.16 (m, 4H), 1.52-1.71 (m, 4H).

Compound 279:4-(4-{2-[4-(6-fluoro-naphthalen-2-yl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(CI, m/z): [M+H]⁺ 555.0; ¹H NMR (DMSO-d6): δ 7.75-7.83 (m, 2H), 7.69 (d,J=8.7 Hz, 1H), 7.55 (dd, J=10.2, 2.4 Hz, 1H), 7.46 (d, J=8.9 Hz, 1H),7.31 (td, J=8.9, 2.6 Hz, 1H), 7.26 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.02(s, 1H), 6.85 (d, J=8.8 Hz, 1H), 4.21 (s, 2H), 3.58-3.66 (m, 4H),3.34-3.46 (m, 2H), 3.24 (d, J=17.6 Hz, 4H), 1.99-2.07 (m, 2H), 1.89-1.98(m, 2H), 1.28-1.43 (m, 2H), 1.15-1.28 (m, 2H).

Compound 293:4-[(4-{2-[4-(6-fluoro-naphthalen-2-yl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexyl)-methyl-amino]-2-trifluoromethyl-benzonitrile

(CI, m/z): [M+H]⁺ 569.0; ¹H NMR (CDCl₃): δ 7.65-7.72 (m, 2H), 7.58 (d,J=8.8 Hz, 1H), 7.36 (dd, J=9.8, 2.5 Hz, 1H), 7.29 (dd, J=9.1, 2.2 Hz,1H), 7.21 (td, J=8.8, 2.6 Hz, 1H), 7.13 (d, J=2.5 Hz, 1H), 6.94 (d,J=2.7 Hz, 1H), 6.80 (dd, J=9.0, 2.7 Hz, 1H), 4.26 (s, 2H), 3.75-3.85 (m,4H), 3.66-3.71 (m, 1H), 3.38-3.45 (m, 1H), 3.23-3.30 (m, 4H), 2.86 (s,3H), 2.19-2.29 (m, 2H), 1.75-1.88 (m, 2H), 1.57-1.68 (m, 2H), 1.39-1.52(m, 2H).

Compound 305:4-(4-{2-[4-(3-chloro-5-trifluoromethyl-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(CI, m/z): [M+H]⁺ 643.0; ¹H NMR (CDCl₃): δ 7.76-7.90 (m, 1H), 7.47-7.65(m, 3H), 6.78 (d, J=2.0 Hz, 1H), 6.62 (dd, J=8.6, 2.1 Hz, 1H), 4.27 (d,J=7.5 Hz, 1H), 4.15 (s, 2H), 3.82 (s, 2H), 3.61-3.70 (m, 2H), 3.53-3.60(m, 2H), 3.23-3.44 (m, 2H), 2.58 (br. s., 4H), 1.99-2.18 (m, 4H),1.34-1.51 (m, 2H), 1.12-1.32 (m, 2H).

Compound 306:4-(4-{2-oxo-2-[4-(5-trifluoromethyl-benzofuran-2-ylmethyl)-piperazin-1-yl]-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(CI, m/z): [M+H]⁺ 609.0; ¹H NMR (CDCl₃): δ 7.84 (s, 1H), 7.49-7.62 (m,3H), 6.81 (d, J=2.0 Hz, 1H), 6.70 (s, 1H), 6.65 (dd, J=8.6, 2.2 Hz, 1H),4.27 (d, J=7.7 Hz, 1H), 4.19 (s, 2H), 3.76 (s, 2H), 3.65-3.72 (m, 2H),3.57-3.63 (m, 2H), 3.28-3.46 (m, 2H), 2.57 (t, J=4.9 Hz, 4H), 2.05-2.22(m, 4H), 1.36-1.51 (m, 2H), 1.15-1.32 (m, 2H).

Compound 307:1-[(2R,5S)-4-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-2,5-dimethyl-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone(mixture of stereoisomers)

(CI, m/z): [M+H]⁺ 609.0; ¹H NMR (CDCl₃): δ 8.02 (d, J=9.0 Hz, 1H),6.82-6.93 (m, 2H), 6.74-6.82 (m, 1H), 6.59-6.68 (m, 2H), 4.80-4.99 (m,1H), 4.53 (d, J=7.6 Hz, 1H), 4.06-4.31 (m, 3H), 3.85-4.04 (m, 1H),3.33-3.53 (m, 3H), 3.18-3.32 (m, 2H), 2.99-3.13 (m, 2H), 2.83-2.94 (m,1H), 2.58-2.80 (m, 2H), 2.38-2.56 (m, 1H), 2.15 (d, J=9.7 Hz, 4H),1.41-1.55 (m, 2H), 1.21-1.39 (m, 4H), 1.14 (d, J=5.4 Hz, 1H), 0.88-1.05(m, 3H).

Compound 308:4-(4-{2-[(2R,5S)-4-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-2,5-dimethyl-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile(mixture of stereoisomers)

(CI, m/z): [M+H]⁺ 589.0; ¹H NMR (CDCl₃): δ 7.54 (d, J=8.5 Hz, 1H), 6.87(d, J=8.0 Hz, 1H), 6.80-6.84 (m, 1H), 6.77 (dd, J=8.3, 3.7 Hz, 1H),6.60-6.70 (m, 2H), 4.78-4.99 (m, 1H), 4.40 (d, J=7.6 Hz, 1H), 4.07-4.28(m, 2H), 3.31-3.54 (m, 3H), 3.18-3.31 (m, 1H), 3.07 (d, J=8.0 Hz, 2H),2.88 (d, J=11.2 Hz, 1H), 2.57-2.79 (m, 2H), 2.37-2.55 (m, 1H), 2.13 (m,6H), 1.36-1.55 (m, 3H), 1.20-1.35 (m, 3H), 1.13 (d, J=4.9 Hz, 1H),0.85-1.05 (m, 3H).

Compound 309:1-[5-(5-fluoro-2,3-dihydro-benzofuran-2-ylmethyl)-2,5-diaza-bicyclo[2.2.2]oct-2-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 607.0; ¹H NMR (CDCl₃): δ 8.02 (d, J=9.0 Hz, 1H),6.83-6.91 (m, 2H), 6.73-6.82 (m, 1H), 6.60-6.69 (m, 2H), 4.81-4.96 (m,1H), 4.45-4.58 (m, 1H), 4.07-4.20 (m, 3H), 3.85 (overlapping m, 2H),3.50 (d, J=5.2 Hz, 2H), 3.34-3.46 (m, 3H), 3.16-3.31 (m, 1H), 3.02-3.13(m, 2H), 2.92-3.01 (m, 2H), 2.77-2.90 (m, 1H), 2.08-2.25 (m, 4H),1.76-1.98 (m, 1H), 1.39-1.57 (m, 1H), 1.16-1.36 (m, 4H).

Compound 312:1-[4-(3-chloro-5-fluoro-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 613.0; ¹H NMR (CDCl₃): δ 8.02 (d, J=9.0 Hz, 1H), 7.41(dd, J=9.0, 3.9 Hz, 1H), 7.22 (dd, J=7.9, 2.6 Hz, 1H), 7.07 (td, J=9.0,2.6 Hz, 1H), 6.85 (d, J=2.3 Hz, 1H), 6.63 (dd, J=9.0, 2.5 Hz, 1H), 4.49(d, J=7.5 Hz, 1H), 4.18 (s, 2H), 3.80 (s, 2H), 3.63-3.73 (m, 2H),3.53-3.62 (m, 2H), 3.30-3.48 (m, 2H), 2.59 (t, J=4.7 Hz, 4H), 2.02-2.22(m, 4H), 1.36-1.54 (m, 2H), 1.16-1.34 (m, 2H)

Compound 313:4-(4-{2-[4-(3-chloro-5-fluoro-benzofuran-2-ylmethyl)-piperazin-1-yl]-2-oxo-ethoxy}-cyclohexylamino)-2-trifluoromethyl-benzonitrile

(CI, m/z): [M+H]⁺ 593.0; ¹H NMR (CDCl₃): δ 7.55 (d, J=8.6 Hz, 1H), 7.42(dd, J=8.9, 3.9 Hz, 1H), 7.22 (dd, J=7.9, 2.5 Hz, 1H), 7.07 (td, J=9.0,2.6 Hz, 1H), 6.81 (d, J=2.1 Hz, 1H), 6.65 (dd, J=8.6, 2.2 Hz, 1H),4.25-4.35 (m, 1H), 4.18 (s, 2H), 3.80 (s, 2H), 3.64-3.72 (m, 2H),3.53-3.62 (m, 2H), 3.26-3.49 (m, 2H), 2.51-2.68 (m, 4H), 2.04-2.22 (m,5H), 1.36-1.52 (m, 2H), 1.15-1.31 (m, 2H).

Compound 314:1-[4-(6-hydroxy-naphthalen-2-yl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 573.0; ¹H NMR (DMSO-d6): δ 8.05 (d, J=9.2 Hz, 1H),7.57 (dd, J=5.6, 4.8 Hz, 2H), 7.45 (br. s., 1H), 7.27 (dd, J=9.0, 1.6Hz, 1H), 7.08 (d, J=14.1 Hz, 2H), 6.94-7.02 (m, 2H), 6.85 (dd, J=9.3,2.3 Hz, 1H), 4.21 (s, 2H), 3.62 (br s, 4H), 3.43-3.53 (m, 1H), 3.36-3.42(m, 1H), 3.01-3.23 (m, 4H), 1.89-2.10 (m, 4H), 1.38 (m, 2H), 1.25 (m,2H).

Example 28 Preparation of Compound 111

Step 1. Formation of 1-[4-(trifluoromethyl)phenyl]piperazine

The mixture of 1-bromo-4-(trifluoromethyl)benzene (15 g, 67 mmol),piperazine (28.8 g, 334.4 mmol, 5 eq.), Pd₂(dba)₃ (1.4 g, 1.53 mmol, 2mol %), BINAP (420 mg, 0.67 mmol, 1 mol %) and t-BuONa (12.9 g, 134.2mmol, 2 eq.) in toluene (200 ml) was stirred for 2 hours at 70° C. undernitrogen. Then the solids were filtered off and the mixture wasconcentrated under vacuum to give a residue, which was purified bysilica gel column chromatography using 1% 5% methanol in dichloromethaneto afford 1-[4-(trifluoromethyl)phenyl]piperazine as a dark red solid(10.5 g, 68%). (ES, m/z): [M+H]⁺ 231.1; ¹H NMR (300 MHz, CDCl₃): δ 7.48(d, J=8.7 Hz, 2H), 6.92 (d, J=8.7 Hz, 2H), 3.32-3.20 (m, 4H), 3.04-3.01(m, 4H).

Step 2. Formation of2-chloro-1-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yf]ethan-1-one

To a mixture of 1-[4-(trifluoromethyl)phenyl]piperazine (600 mg, 2.61mmol) and triethylamine (660 mg, 6.52 mmol) in dichloromethane (20 ml)was added 2-chloroacetyl chloride (380 mg, 3.36 mmol) dropwise at 0° C.The resulting solution was stirred for 1 hour at room temperature. Thereaction mixture was then quenched by water (80 ml) and extracted withdichloromethane (3×30 ml). The organic layers were combined, dried overanhydrous magnesium sulfate, and concentrated under vacuum. The residuewas purified by silica gel column chromatography using 1-10% ethylacetate in petroleum ether to afford2-chloro-1-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]ethan-1-one as awhite solid (479 mg, 60%). (ES, m/z): [M+H]⁺ 307.1; ¹H NMR (300 MHz,CDCl₃): δ 7.52 (d, J=8.4 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.12 (s, 1H),3.81 (t, J=5.1 Hz, 2H), 3.72 (t, J=5.1 Hz, 2H), 3.36 (t, J=5.1 Hz, 2H),3.30 (t, J=5.1 Hz, 2H).

Step 3. Formation of 7-methoxynaphthalen-2-ol

To a mixture of naphthalene-2,7-diol (25 g, 156.08 mmol) and K₂CO₃ (32.3g, 232.02 mmol) in acetone (300 ml) was added iodomethane (22.2 g,156.41 mmol) dropwise with stirring at 0° C. The resulting solution wasstirred overnight at room temperature. The solids were filtered off andthe filtrate was concentrated under vacuum to give a residue, which waspurified by silica gel column chromatography using 1%-10% ethyl acetatein petroleum ether to afford 7-methoxynaphthalen-2-ol as a light yellowsolid (10 g, 37%). (ES, m/z): [M+H]⁺ 175.1; ¹H NMR (400 MHz, DMSO-d6): δ9.65 (s, 1H), 7.65 (d, J=8.8 Hz, 2H), 6.79 (dd, J=13.6, 1.6 Hz, 2H),6.92-6.89 (m, 2H), 3.84 (s, 3H).

Step 4. Formation of 7-methoxynaphthalen-2-amine

The solution of 7-methoxynaphthalen-2-ol (6.5 g, 37.31 mmol) and NaHSO₃(11.6 g, 111.54 mmol) in ammonium hydroxide (100 ml) was stirred for 2days at 140° C. in a sealed tube and then cooled to room temperature.The solids were collected by filtration to afford7-methoxynaphthalen-2-amine as an off-white solid (4.5 g, 70%). (ES,m/z): [M+H]⁺ 174.1; ¹H NMR (300 MHz, CDCl₃): δ 7.57 (d, J=8.7 Hz, 2H),6.97-6.87 (m, 3H), 6.79 (dd, J=8.7, 2.1 Hz, 1H), 3.90 (s, 3H), 3.84 (brs, 2H).

Step 5. Formation of 1-iodo-7-methoxynaphthalen-2-amine

To a mixture of 7-methoxynaphthalen-2-amine (5 g, 29 mmol) and sodiumcarbonate (6.1 g, 57.6 mmol) in tetrahydrofuran (200 ml) and water (20ml) was added iodine (7.0 g, 27.67 mmol) in portions at 0° C. Theresulting solution was stirred overnight at room temperature and thendiluted with water (250 ml), extracted with ethyl acetate (3×200 ml).The combined organic layers were dried over anhydrous magnesium sulfate,filtered, and concentrated under vacuum to give a residue, which waspurified by silica gel column chromatography using 5% ethyl acetate inpetroleum ether to afford 1-iodo-7-methoxynaphthalen-2-amine as a yellowsolid (5.2 g, 60%). (ES, m/z): [M+H]⁺ 300.1; ¹H NMR (300 MHz, CDCl₃): δ7.54 (dd, J=8.7, 5.4 Hz, 2H), 7.30 (d, J=2.4 Hz, 1H), 6.91 (dd, J=8.7,2.4 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 4.04 (br s, 2H), 3.96 (s, 3H).

Step 6. Formation of 1-iodo-7-methoxy-2-nitronaphthalene

To a solution of 1-iodo-7-methoxynaphthalen-2-amine (10 g, 33.43 mmol)and potassium iodide (300 mg, 1.81 mmol) in acetonitrile (150 ml) wasadded dropwise TBHP (12 mL) with stirring. The resulting solution wasrefluxed for 3 days, then quenched by saturated aqueous Na₂S₂O₃ (50 ml)and extracted with ethyl acetate (3×150 ml). The combined organic layerswere dried over anhydrous magnesium sulfate, filtered, and concentratedunder vacuum to give a residue, which was purified by silica gel columnchromatography using 1%-10% ethyl acetate in petroleum ether to afford1-iodo-7-methoxy-2-nitronaphthalene as a yellow solid (2.5 g, 23%). ¹HNMR (300 MHz, CDCl₃): δ 7.86 (d, J=8.7 Hz, 1H), 7.78 (dd, J=9.0, 1.8 Hz,1H), 7.68 (d, J=2.4 Hz, 1H), 7.54 (dd, J=8.7, 1.8 Hz, 1H), 7.78 (dd,J=9.0, 2.4 Hz, 1H), 4.04 (s, 3H).

Step 7. Formation of 7-methoxy-2-nitro-1-(trifluoromethyl)naphthalene

The mixture of 1-iodo-7-methoxy-2-nitronaphthalene (3.7 g, 11.24 mmol),CuI (2.3 g, 12.08 mmol) and KF (1 g, 17.24 mmol) inN,N-dimethylformamide (50 ml) was stirred for 0.5 h at 120° C. beforethe addition of 2,2-difluoro-2-(fluorosulfonyl)acetate (2.3 g, 11.97mmol). The resulting solution was stirred for another 0.5 h at 120° C.and then quenched by water (300 ml). The crude product was extractedwith dichloromethane (3×100 ml) and the organic fractions were combinedand washed by brine (3×150 ml). The organic layers were dried overanhydrous magnesium sulfate, filtered, and concentrated under vacuum togive a residue, which was purified by silica gel column chromatographyusing 1%-10% ethyl acetate in petroleum ether to afford7-methoxy-2-nitro-1-(trifluoromethyl)naphthalene as a off-white solid (2g, 66%). ¹H NMR (300 MHz, DMSO): δ 8.48 (d, J=8.7 Hz, 1H), 8.21 (d,J=9.3 Hz, 1H), 7.84 (d, J=8.7 Hz, 1H), 7.56 (dd, J=9.0, 2.1 Hz, 1H),7.41 (s, 1H), 3.96 (s, 3H).

Step 8. Formation of 7-amino-8-(trifluoromethyl)naphthalen-2-ol

To a solution of 7-methoxy-1-(trifluoromethyl)naphthalen-2-amine (2 g,8.29 mmol) in dichloromethane (20 ml) was added dropwise BBr₃ (4 ml, 42mmol, 5 eq.) with stirring at −78° C. The resulting solution was stirredovernight at room temperature and then quenched by ice-water (50 ml) andextracted with dichloromethane (3×50 ml). The combined organic layerswere dried over anhydrous magnesium sulfate, filtered, and concentratedunder vacuum to afford 7-amino-8-(trifluoromethyl)naphthalen-2-ol as abrown solid (1.3 g, 69%).

(ES, m/z): [M−H]⁻ 256.0; ¹H NMR (300 MHz, DMSO-d6): δ 10.16 (s, 1H),8.41 (d, J=8.7 Hz, 1H), 8.13 (d, J=9.0 Hz, 1H), 7.73 (d, J=8.7 Hz, 1H),7.47 (s, 1H), 7.40 (dd, J=9.0, 2.1 Hz, 1H).

Step 9. Formation of2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]-1-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]ethan-1-one(#111)

The mixture of 7-nitro-8-(trifluoromethyl)naphthalen-2-ol (50 mg, 0.19mmol), 2-chloro-1-4-[4-(trifluoromethyl)phenyl]piperazin-1-ylethan-1-one(65.4 mg, 0.21 mmol, 1.1 eq.) and potassium carbonate (29.5 mg, 0.21mmol, 1.1 eq.) in acetonitrile (15 ml) was heated at reflux for 5 hours.The solids were filtered off and the filtrate was concentrated undervacuum to give a residue, which was purified by silica gel columnchromatography using methanol in dichloromethane to afford2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]-1-[4-[4-(trifluoromethyl)phenyl]piperazin-1-yl]ethan-1-oneas a light yellow solid (46.8 mg, 46%). (ES, m/z): [M+H]⁺ 528.10; ¹H NMR(400 MHz, CDCl₃): δ 8.07 (d, J=8.8 Hz, 1H), 6.92 (d, J=9.2 Hz, 1H),7.55-7.38 (m, 5H), 6.95 (d, J=8.4 Hz, 2H), 4.93 (s, 2H), 3.84-3.82 (m,4H), 3.34-3.29 (m, 4H).

Compound 112:1-[4-(4-chlorophenyl)piperazin-1-yl]-2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 493.85; ¹H NMR (400 MHz, CDCl₃): δ 8.08 (d, J=8.8 Hz,1H), 7.92 (d, J=8.8 Hz, 1H), 7.56 (s, 1H), 7.45 (d, J=9.2 Hz, 1H), 7.40(d, J=8.8 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 6.99 (d, J=8.4 Hz, 2H), 4.92(s, 2H), 3.91-3.86 (m, 4H), 3.24-3.19 (m, 4H).

Compound 113:2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]-1-[4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl]ethan-1-one

(ES, m/z): [M+H]⁺ 529.05; ¹H NMR (400 MHz, CDCl₃): δ 8.42 (s, 1H), 8.07(d, J=8.8 Hz, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.71 (dd, J=9.2, 2.0 Hz, 1H),7.56 (s, 1H), 7.46 (d, J=8.8 Hz, 1H), 7.40 (d, J=8.4 Hz, 1H), 6.69 (d,J=8.8 Hz, 1H), 4.93 (s, 2H), 3.83-3.76 (m, 6H), 3.66-3.64 (m. 2H).

Compound 114:1-[4-(5-chloropyridin-2-yl)piperazin-1-yl]-2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 495.00; ¹H NMR (400 MHz, CDCl₃): δ 8.16 (d, J=2.4 Hz,1H), 8.07 (d, J=8.8 Hz, 1H), 7.91 (d, J=9.2 Hz, 1H), 7.58-7.55 (m, 2H),7.45 (dd, J=9.2, 2.4 Hz, 1H), 7.40 (d, J=8.8 Hz, 1H), 6.69 (d, J=9.2 Hz,1H), 4.92 (s, 2H), 3.81 (br s, 6H), 3.56 (br s, 2H).

Compound 127:1-[4-(naphthalen-2-yl)piperazin-1-yl]-2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 510.05; ¹H NMR (300 MHz, CDCl₃): δ 8.07 (d, J=8.7 Hz,1H), 7.92 (d, J=9.0 Hz, 1H), 7.78-7.69 (m, 3H), 7.57 (s, 1H), 7.49-7.31(m, 4H), 7.28 (m, 1H), 7.16 (s, 1H), 4.94 (s, 2H), 3.89-3.83 (m, 4H),3.34-3.29 (m, 4H).

Compound 128:1-[4-(6-fluoronaphthalen-2-yl)piperazin-1-yl]-2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 528.00; ¹H NMR (400 MHz, CDCl₃): δ 8.07 (d, J=8.4 Hz,1H), 7.92 (d, J=9.2 Hz, 1H), 7.78-7.73 (m, 2H), 7.58 (s, 1H), 7.47 (d,J=8.8 Hz, 1H), 7.41-7.36 (m, 3H), 7.32 (d, J=9.2 Hz, 1H), 7.23-7.20 (m,1H), 4.94 (s, 2H), 3.93-3.88 (m, 4H), 3.33-3.28 (m, 4H).

Compound 129:2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]-1-[4-(quinolin-2-yl)piperazin-1-yl]ethan-1-one

(ES, m/z): [M+H]⁺ 511.25; ¹H NMR (400 MHz, CDCl₃): δ 8.08 (d, J=8.8 Hz,1H), 8.06-7.94 (m, 1H), 7.91 (d, J=8.8 Hz, 1H), 7.71-7.60 (m, 3H), 7.57(s, 1H), 7.47 (d, J=9.2 Hz, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.38-7.31 (m,1H), 7.00 (d, J=9.2 Hz, 1H), 4.95 (s, 2H), 4.02-3.77 (m, 8H).

Compound 130:1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 545.25; ¹H NMR (300 MHz, CDCl₃): δ 8.06 (d, J=8.7 Hz,1H), 7.91 (d, J=9.3 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.65-7.57 (m, 3H),7.51-7.48 (m, 2H), 7.39 (d, J=9.0 Hz, 1H), 7.00 (d, J=9.3 Hz, 1H), 4.94(s, 2H), 3.87-3.74 (m, 8H).

Compound 131:2-[[7-nitro-8-(trifluoromethyl)naphthalen-2-yl]oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one

(ES, m/z): [M+H]⁺ 579.00; ¹H NMR (300 MHz, CDCl₃): δ 8.10 (d, J=8.7 Hz,1H), 8.02 (d, J=9.0 Hz, 1H), 7.96-7.93 (m, 2H), 7.85-7.75 (m, 2H), 7.60(s, 1H), 7.50 (dd, J=9.3, 2.1 Hz, 1H), 7.42 (d, J=8.7 Hz, 1H), 7.08 (d,J=9.0 Hz, 1H), 4.98 (s, 2H), 3.99-3.89 (m, 2H), 3.85-3.80 (m, 6H).

Compound 180:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one

(ES, m/z): [M+H]⁺ 629.10; ¹H NMR (300 MHz, CDCl₃): δ 8.01 (d, J=9.0 Hz,1H), 7.85 (s, 1H), 7.56 (s, 2H), 6.84 (d, J=2.4 Hz, 1H), 6.70 (s, 1H),6.60 (dd, J=2.7 Hz, 9.0 Hz, 1H), 4.42 (d, J=7.5 Hz, 1H), 4.18 (s, 2H),3.60-3.90 (m, 5H), 3.36-3.40 (m, 3H), 2.55 (br s, 4H), 2.09-2.14 (m,4H), 1.38-1.56 (m, 2H), 1.19-1.30 (m, 2H).

Compound 181:1-[4-[(5-chloro-1-benzofuran-2-yl)carbonyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 609.00; ¹H NMR (400 MHz, CDCl₃): δ 8.04 (d, J=8.8 Hz,1H), 7.67 (d, J=1.5 Hz, 1H), 7.47 (dd, J=1.6, 8.8 Hz, 1H), 7.41 (dd,J=2.0, 8.8 Hz, 1H), 7.32 (s, 1H), 6.88 (s, 1H), 6.67 (d, J=7.6 Hz, 1H),4.27 (s, 2H), 3.80 (br s, 4H), 3.60-3.76 (m, 4H), 3.39-3.48 (m, 2H),2.07-2.19 (m, 4H), 1.49-1.54 (m, 2H), 1.28-1.36 (m, 2H).

Compound 182:1-[4-[(5-fluoro-1-benzofuran-2-yl)carbonyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 593.15; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.47 (dd, J=4.2 Hz, 9.3 Hz, 1H), 7.26-7.36 (m, 2H), 7.11-7.19 (m,1H), 6.86 (s, 1H), 6.65 (d, J=9.9 Hz, 1H), 4.25 (s, 2H), 3.91 (br s,4H), 3.65-3.79 (m, 4H), 3.39-3.45 (m, 2H), 2.14-2.20 (m, 4H), 1.43-1.54(m, 2H), 1.28-1.35 (m, 2H).

Compound 183: 2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexan-1-e)oxy]-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]carbonyl]piperazin-1-yl)ethan-1-one

(ES, m/z): [M+H]⁺ 643.00; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (m, 2H),7.71-7.61 (m, 2H), 7.44 (s, 1H), 6.87 (s, 1H), 6.68 (d, J=9.6 Hz, 1H),4.25 (s, 2H), 3.98-3.82 (br s, 4H), 3.80-3.68 (m, 4H), 3.52-3.37 (m,2H), 2.17-2.05 (m, 4H), 1.53-1.43 (m, 2H), 1.37-1.25 (m, 2H).

1-[4-[(5-chloro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)ethan-1-one(#184)

(ES, m/z): [M+H]⁺ 589.05; ¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, J=9.0 Hz,1H), 7.49 (d, J=1.8 Hz, 1H), 7.39 (d, J=8.7 Hz, 1H), 7.21-7.25 (m, 1H),7.09-7.11 (m, 3H), 6.95 (m, 2H), 6.89 (dd, J=2.4, 9.0 Hz, 1H), 6.56 (s,1H), 6.31 (s, 1H), 4.71 (s, 2H), 3.55-3.66 (overlapping m, 6H), 2.56 (brs, 4H).

Compound 185:1-[4-[(5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)ethan-1-one

(ES, m/z): [M+H]⁺ 575.25; ¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, J=9.0 Hz,1H), 7.11-7.16 (m, 3H), 6.98 (m, 2H), 6.82-6.92 (m, 2H), 6.75-6.79 (m,1H), 6.65 (dd, J=4.2 Hz, 8.7 Hz, 1H), 6.41 (s, 1H), 4.99 (m, 1H), 4.73(s, 2H), 3.63-3.70 (m, 4H), 3.26 (dd, J=9.3, 15.6 Hz, 1H), 2.95 (dd,J=7.8, 15.9 Hz, 1H), 2.78 (dd, J=7.8, 13.2 Hz, 1H), 2.59-2.63 (m, 5H).

Compound 186:1-[4-[(5-fluoro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenyl)ethan-1-one

(ES, m/z): [M+H]⁺ 573.20; ¹H NMR (300 MHz, CDCl₃): δ 7.96 (d, J=9.0 Hz,1H), 7.42 (dd, J=4.2 Hz, 9.0 Hz, 1H), 7.18 (dd, J=2.4, 8.4 Hz, 1H),7.17-7.09 (m, 3H), 6.99 (m, 3H), 6.90 (dd, J=2.4, 9.0 Hz, 1H), 6.63 (s,1H), 6.30 (s, 1H), 4.72 (s, 2H), 3.81-3.62 (m, 6H), 2.57 (br s, 4H).

Compound 187:2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)-1-(4-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one

(ES, m/z): [M+H]⁺ 525.25; ¹H NMR (300 MHz, CDCl₃): δ 7.97 (d, J=9.0 Hz,1H), 7.39 (overlapping s & d, 2H), 7.11-7.15 (m, 3H), 7.01 (m, 2H),6.89-6.93 (dd, J=2.4, 9.0 Hz, 1H), 6.83 (d, J=8.1 Hz, 1H), 6.29 (s, 1H),5.01 (m, 1H), 4.73 (s, 2H), 3.64-3.70 (m, 4H), 3.33 (dd, J=9.0, 15.9 Hz,1H), 3.00 (dd, J=9.3, 15.9 Hz, 1H), 2.79 (dd, J=7.2, 13.2 Hz, 1H),2.49-2.63 (m, 5H).

Example 29 Preparation of Compound 188

Steps 1-6

Starting from the THP-protected 4-(trifluoromethyl)phenol,2-chloro-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-onewas made in a manner analogous to what was described in the synthesis ofcompound 184.

Step 7. Formation of2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one(#188)

To a solution of2-chloro-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methy1]piperazin-1-yl)ethan-1-one (100 mg, 0.28 mmol) in acetonitrile (10 ml)was added potassium carbonate (57.5 mg, 0.42 mmol) and4-[4-nitro-3-(trifluoromethyl)phenyl]aminophenol (83 mg, 0.28 mmol). Themixture was stirred and heated at 80° C. (oil bath) for 3 hours. Thesolids were filtered off and the filtrate was concentrated under vacuumto give a residue, which was purified by Prep-TLC with 60% ethyl acetatein petroleum ether to afford2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-oneas a yellow solid (125.8 mg, 73%); (ES, m/z): [M+H]⁺ 623.20; ¹H NMR (400MHz, CDCl₃): δ 8.00 (d, J=8.8 Hz, 1H), 7.86 (s, 1H), 7.60 (m, 2H), 7.14(overlapping s & d, 3H), 7.00 (d, J=8.4 Hz, 2H), 6.92 (d, J=8.8 Hz, 1H),6.72 (s, 1H), 6.29 (s, 1H), 4.74 (s, 2H), 3.91-3.53 (m, 6H), 2.60 (br s,4H).

Compound 189:1-[4-[(5-chloro-1-benzofuran-2-yl)carbonyl]piperazin-1-yl]-2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)ethan-1-one

(ES, m/z): [M+H]⁺ 603.00; ¹H NMR (300 MHz, CDCl₃): δ 7.99 (d, J=9.0 Hz,1H), 7.65 (d, J=1.8 Hz, 1H), 7.45 (d, J=9.0 Hz, 1H), 7.38 (dd, J=2.1,9.0 Hz, 1H), 7.33 (s, 1H), 7.14-7.18 (m, 3H), 7.01 (d, J=9.0 Hz, 2H),6.90 (dd, J=2.7 Hz, 9.0 Hz, 1H), 6.24 (br s, 1H), 4.78 (s, 2H), 3.88 (brs, 4H), 3.77 (br s, 4H).

Compound 190: 4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenyl4-[(5-fluoro-1-benzofuran-2-yl)carbonyl]piperazine-1-carboxylate

(ES, m/z): [M+H]⁺ 587.15; ¹H NMR (300 MHz, CDCl₃): δ 7.98 (d, J=9.0 Hz,1H), 7.49 (dd, J=3.6, 8.7 Hz, 1H), 7.45-7.31 (m, 2H), 7.15 (overlappingm, 4H), 7.01 (d, J=8.7 Hz, 2H), 6.92 (d, J=9.0 Hz, 1H), 6.38 (s, 1H),4.79 (s, 2H), 3.90 (br s, 4H), 3.78 (br s, 4H).

Compound 191:2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)-1-(4-[[5-(trifluoromethyl)-1-benzofuran-2-yl]carbonyl]piperazin-1-yl)ethan-1-one

(ES, m/z): [M+H]⁺ 637.10; ¹H NMR (300 MHz, DMSO-d6): δ 9.39 (s, 1H),8.21 (s, 1H), 8.10 (d, J=9.0 Hz, 1H), 7.93 (d, J=8.7 Hz, 1H), 7.81 (d,J=8.7 Hz, 1H), 7.57 (s, 1H), 7.19-7.24 (m, 3H), 7.00-7.09 (m, 3H), 4.91(s, 2H), 3.70-3.97 (m, 4H), 3.55-3.70 (m, 4H).

2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]-1-(1,2,3,4-tetrahydroisoquinolin-2-yl)ethan-1-one(#192)

(ES, m/z): [M+H]⁺ 478.10; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.22-7.17 (m, 4H), 6.84 (s, 1H), 6.64 (d, J=9.0 Hz, 1H), 4.74 (m,2H), 4.28 (s, 2H), 3.84-3.72 (m, 2H), 3.51-3.33 (m, 2H), 2.97-2.84 (m,2H), 2.13 (m, 4H), 1.50-1.43 (m, 2H), 1.29-1.25 (m, 2H).

Example 30 Preparation of Compound 193

Step 1. Formation of 6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-one

To a solution of 5-fluoro-2,3-dihydro-1H-inden-1-one (4.5 g, 29.97 mmol)in dichloromethane (50 ml) was added methanesulfonic acid (40 ml). Thiswas followed by the addition of sodium azide (2.73 g, 42.0 mmol) inseveral batches with stirring over 2 hours at 0° C. The reaction mixturewas then quenched with aqueous sodium hydroxide and extracted withdichloromethane (2×100 ml). The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum togive a residue, which was purified by silica gel column chromatographyusing 10% 100% ethyl acetate in petroleum ether to afford6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-one as a white solid (2.5 g,51%); (ES, m/z): [M+H]⁺ 166; ¹H NMR (300 MHz, CDCl₃): δ 8.11 (dd, J=6.0,8.7 Hz, 1H), 7.07-7.00 (m, 1H), 6.94 (dd, J=2.4, 8.7 Hz, 1H), 6.57 (brs, 1H), 3.61 (t, J=6.6, 2H), 3.03 (t, J=6.6, 2H).

Step 2. Formation of 6-fluoro-1,2,3,4-tetrahydroisoquinoline

6-fluoro-1,2,3,4-tetrahydroisoquinolin-1-one (100 mg, 0.61 mmol) wasstirred in a solution of BH₃.THF (15 ml) for 2 hours at 70° C. (oilbath). To the mixture was added 5 ml of methanol. The solvent was thenremoved and the residue was heated at 105° C. in aqueous hydrochloricacid (30 ml, 1M) for 2 hours. The reaction mixture was cooled, basifiedwith aqueous saturated sodium bicarbonate solution, and extracted withethyl acetate (2×30 ml). The organic fractions were combined, dried overanhydrous sodium sulfate, filtered, and evaporated to afford6-fluoro-1,2,3,4-tetrahydroisoquinoline as yellow oil (60 mg, 66%); (ES,m/z): [M+H]⁺ 152; ¹H NMR (300 MHz, DMSO-d6): δ 7.05 (t, J=7.2, 1H),6.94-6.87 (m, 2H), 3.79 (s, 2H), 2.92 (t, J=6.0, 2H), 2.69 (t, J=5.7,2H).

Step 3. Formation of1-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one(#193)

To a solution of2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]aceticacid (144 mg, 0.40 mmol) in dichloromethane (15 ml) was added EDAC.HCl(114 mg, 0.59 mmol), HOBt (80 mg, 0.59 mmol) and triethylamine (120 mg,1.19 mmol) with stirring for 30 minutes. Then6-fluoro-1,2,3,4-tetrahydroisoquinoline (60 mg, 0.40 mmol) was added tothe reaction mixture and the contents were stirred overnight at roomtemperature. The reaction mixture was diluted with water (100 ml) andextracted with dichloromethane (3×80 ml). The organic fractions werecombined, dried over anhydrous sodium sulfate, filtered, and evaporatedto give a residue, which was purified by silica gel columnchromatography using 5% ethyl acetate in dichloromethane to afford1-(6-fluoro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-oneas a yellow solid (93.8 mg, 48%); (ES, m/z): [M+H]⁺ 496.00; ¹H NMR (300MHz, CDCl₃): δ 8.01 (d, J=9.0 Hz, 1H), 7.09 (m, 1H), 6.95-6.82 (m, 3H),6.65 (d, J=9.0 Hz, 1H), 4.69 (m, 2H), 4.28 (s, 2H), 3.84-3.70 (m, 2H),3.48-3.33 (m, 2H), 2.93-2.83 (m, 2H), 2.16-2.13 (m, 4H), 1.52-1.40 (m,2H), 1.34-1.16 (m, 2H).

2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[6-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinolin-2-yl]ethan-1-one(#194)

(ES, m/z): [M+H]⁺ 546.00; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.57-7.42 (m, 2H), 7.28-7.22 (m, 1H), 6.84 (s, 1H), 6.64 (d, J=9.0Hz, 2H), 4.78 (s, 2H), 4.29 (s, 2H), 3.91-3.73 (m, 2H), 3.46-3.36 (m,2H), 3.00-2.89 (m, 2H), 2.20-2.10 (m, 4H), 1.54-1.38 (m, 2H), 1.34-1.14(m, 2H).

Compound 195:1-(6-chloro-1,2,3,4-tetrahydroisoquinolin-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 512.10; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.20-7.16 (m, 2H), 7.10-7.05 (m, 1H), 6.84 (s, 1H), 6.64 (d, J=8.7Hz, 1H), 4.69 (m, 2H), 4.27 (s, 2H), 3.84-3.72 (m, 2H), 3.45-3.39 (m,2H), 2.92-2.85 (m, 2H), 2.16-2.13 (m, 4H), 1.53-1.42 (m, 2H), 1.30-1.26(m, 2H).

Compound 200:N-(naphthalen-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetamide

(ES, m/z): [M+H]⁺ 488.05; ¹H NMR (300 MHz, CDCl₃): δ 8.45 (s, 1H), 8.25(d, J=1.5 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.84-7.78 (m, 3H), 7.55-7.39(m, 3H), 6.87 (d, J=2.1 Hz, 1H), 6.67 (dd, J=2.4, 9.0 Hz, 1H), 4.16 (s,2H), 3.54-3.41 (m, 2H), 2.22 (m, 4H), 1.65-1.52 (m, 2H), 1.39-1.20 (m,2H).

Compound 201:N-(6-fluoronaphthalen-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetamide

(ES, m/z): [M+H]⁺ 506.10; ¹H NMR (300 MHz, CDCl₃): δ 8.45 (s, 1H), 8.31(d, J=2.1 Hz, 1H), 8.07 (d, J=9.0 Hz, 1H), 7.86-7.78 (m, 2H), 7.58 (dd,J=1.8, 8.7 Hz, 1H), 7.47 (dd, J=2.7, 9.9 Hz, 1H), 7.33-7.26 (m, 1H),6.91 (d, J=2.4 Hz, 1H), 6.71 (dd, J=2.4, 9.0 Hz, 1H), 4.20 (s, 2H),3.59-3.45 (m, 2H), 2.27 (m, 4H), 1.68 (m, 2H), 1.43-1.29 (m, 2H).

Compound 202:2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]-N-[6-(trifluoromethyl)naphthalen-2-yl]acetamide

(ES, m/z): [M+H]⁺ 556.10; ¹H NMR (300 MHz, CDCl₃): δ 8.51 (s, 1H), 8.38(s, 1H), 8.10 (s, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.93 (d, J=8.7 Hz, 2H),7.66 (td, J=2.1, 9.3 Hz, 2H), 6.87 (d, J=2.4 Hz, 1H), 6.68 (dd, J=2.4,9.0 Hz, 1H), 4.18 (s, 2H), 3.57-3.41 (m, 2H), 2.25 (m, 4H), 1.65-1.55(m, 2H), 1.37-1.26 (m, 2H).

Compound 203:N-(6-chloronaphthalen-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetamide

(ES, m/z): [M+H]⁺ 522.05; ¹H NMR (300 MHz, CDCl₃): δ 8.44 (s, 1H), 8.27(d, J=1.5 Hz, 1H), 8.03 (d, J=9.0 Hz, 1H), 7.87-7.72 (m, 3H), 7.55 (dd,J=2.1, 8.7 Hz, 1H), 7.43 (dd, J=1.8, 8.7 Hz, 1H), 6.87 (d, J=2.1 Hz,1H), 6.67 (dd, J=2.4, 9.0 Hz, 1H), 4.16 (s, 2H), 3.57-3.39 (m, 2H), 2.23(m, 4H), 1.64-1.53 (m, 2H), 1.40-1.26 (m, 2H).

Compound 208:N-(quinolin-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetamide

(ES, m/z): [M+H]⁺ 489.05; ¹H NMR (300 MHz, DMSO-d6): δ 10.15 (s, 1H),8.39 (d, J=9.0 Hz, 1H), 8.31 (d, J=8.7 Hz, 1H), 8.06 (d, J=9.3 Hz, 1H),7.93 (d, J=5.2 Hz, 1H), 7.83 (d, J=8.4 Hz, 1H), 7.72 (t, J=7.5 Hz, 1H),7.53-7.46 (m, 2H), 7.08 (s, 1H), 6.87 (dd, J=2.1, 9.6 Hz, 1H), 4.23 (s,2H), 3.57-3.47 (m, 2H), 2.16-1.97 (m, 4H), 1.52-1.41 (m, 2H), 1.33-1.25(m, 2H).

Compound 209:N-(6-fluoroquinolin-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetamide

(ES, m/z): [M+H]⁺ 507.05; ¹H NMR (400 MHz, DMSO-d6): δ 10.21 (s, 1H),8.40 (d, J=8.8 Hz, 1H), 8.32 (d, J=8.8 Hz, 1H) 8.07 (d, J=9.2 Hz, 1H),7.88 (dd, J=5.2, 9.2 Hz, 1H), 7.77 (dd, J=2.0, 9.2 Hz, 1H), 7.65 (td,J=2.4, 8.8 Hz, 1H), 7.48 (d, J=7.6 Hz, 1H), 7.08 (s, 1H), 6.87 (d, J=5.2Hz, 1H), 4.23 (s, 2H), 3.55-3.45 (m, 2H), 2.10-1.98 (m, 4H), 1.50-1.42(m, 2H), 1.32-1.23 (m, 2H).

Example 31 Preparation of Compound 210

Steps 1-5

The formation of 2-chloro-6-(trifluoromethyl)quinoline is described inthe synthesis of compound 89.

Step 6. Formation of 6-(trifluoromethyl)quinolin-2-amine

A solution of 2-chloro-6-(trifluoromethyl)quinoline (1 g, 4.3 mmol) inammonium hydroxide (50 ml) was stirred overnight at 130° C. Theresulting mixture was then concentrated under vacuum to give a residue,which was purified by silica gel column chromatography using 1%˜2%methanol in dichloromethane to afford6-(trifluoromethyl)quinolin-2-amine as an off-white solid (350 mg, 38%).(ES, m/z): [M+H]⁺ 212; ¹H NMR (300 MHz, CDCl₃): δ 7.97-7.86 (m, 2H),7.71 (s, 2H), 6.85 (d, J=9.0 Hz, 1H), 5.26 (s, 2H).

Step 7. Formation of2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]-N-[6-(trifluoromethyl)quino-lin-2-yl]acetamide(#210)

To a solution of2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]aceticacid (100 mg, 0.28 mmol) in dichloromethane (30 ml) was added EDAC.HCl(81 mg, 0.42 mmol), HOBt (57 mg, 0.42 mmol) and triethylamine (85 mg,0.84 mmol). After 15 minutes 6-(trifluoromethyl)quinolin-2-amine (68 mg,0.32 mmol) was added and the resulting solution was stirred overnight atroom temperature. The contents were then quenched with water (100 ml)and extracted with dichloromethane (3×50 ml). The organic layers werecombined and dried over anhydrous magnesium sulfate. The solids werefiltered off and the filtrate was concentrated under vacuum to give aresidue, which was purified by silica gel column chromatography using 3%methanol in dichloromethane to afford2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]-oxy]-N-[6-(trifluoromethyl)quinolin-2-yl]acetamideas a yellow solid (80.6 mg, 52%). (ES, m/z): [M+H]⁺ 557.20; ¹H NMR (300MHz, CD₃OD): δ 8.51-8.47 (m, 2H), 8.29 (s, 1H), 8.05-7.99 (m, 2H), 7.93(dd, J=1.8, 9.0 Hz, 1H), 7.01 (d, J=2.4 Hz, 1H), 6.83 (dd, J=2.4, 9.0Hz, 1H), 4.27 (s, 2H), 3.63-3.45 (m, 2H), 2.27-2.14 (m, 4H), 1.70-1.56(m, 2H), 1.46-1.34 (m, 2H).

Compound 211:N-(6-chloroquinolin-2-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]acetamide

(ES, m/z): [M+H]⁺ 523.10; ¹H NMR (300 MHz, DMSO-d6): δ0.24 (s, 1H), 8.39(m, 2H), 8.07 (overlapping d, 2H), 7.83 (d, J=9.0 Hz, 1H), 7.72 (dd,J=2.1, 9.0 Hz, 1H), 7.47 (d, J=8.1 Hz, 1H), 7.08 (s, 1H), 6.88 (d,J=2.4, 9.3 Hz, 1H), 4.23 (s, 2H), 3.3.49 (br m, 2H), 2.0 (br m, 4H),1.51-1.40 (m, 2H), 1.33-1.21 (m, 2H).

N¹-(2,3-dihydro-1-benzofuran-2-ylmethyl)-N²-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]ethanediamide (#216)

(ES, m/z): [M+H]⁺ m/z 551.20; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0Hz, 1H), 7.82 (br s, 1H), 7.73 (br s, 1H), 7.14 (m, 2H), 6.88-6.80 (m,3H), 6.63 (d, J=8.7 Hz, 1H), 4.92-4.85 (m, 1H), 3.83-3.72 (m, 1H),3.60-3.57 (m, 2H), 3.53-3.50 (m, 3H), 3.46-3.31 (m, 3H), 2.91 (dd,J=7.2, 16.2 Hz, 1H), 2.16-2.07 (m, 4H), 1.49-1.41 (m, 2H), 1.29-1.25 (m,2H).

Compound 217:1-[4-[(5-fluoro-2,3-dihydro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-3-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]propan-2-one

(ES, m/z): [M+H]⁺ 569.35; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.79 (br s, 1H), 7.78 (br s, 1H), 6.87-6.78 (m, 3H), 6.71-6.62 (m,2H), 4.92 (m, 1H), 3.74 (m, 1H), 3.58-3.29 (overlapping m, 8H), 2.91(dd, J=7.2, 15.3 Hz, 1H), 2.11 (m, 4H), 1.46-1.42 (m, 2H), 1.29-1.25 (m,2H).

Compound 218:N¹-[(5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl]-N²-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]ethanediamide

(ES, m/z): [M+H]⁺ 585.30; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.79 (m, 1H), 7.71 (m, 1H), 7.11 (s, 1H), 7.07 (dd, J=8.4, 2.1 Hz,1H), 6.84 (s, 1H), 6.69 (d, J=8.4 Hz, 1H), 6.64 (dd, J=2.4, 8.7 Hz, 1H),4.91 (m, 1H), 3.72 (m, 1H), 3.58 (m, 2H), 3.52 (m, 3H), 3.35 (br m, 3H),2.91 (dd, J=7.2, 15.3 Hz, 1H), 2.13 (m, 4H), 1.49-1.41 (m, 2H),1.29-1.25 (m, 2H).

Example 32 Preparation of Compound 219

The formation ofN¹-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]-N²-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]ethanediamide(#219) was conducted in a manner analogous to what was described for thesynthesis of compound 216.

The mixture of lithio([[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]carbamoyl)formate(170 mg, 0.58 mmol), EDAC.HCl (166 mg, 0.87 mmol), HOBt (58.3 mg, 0.43mmol) and triethylamine (87.3 mg, 0.86 mmol) in N,N-dimethylformamide(10 ml) was stirred for 1 hour before the addition ofN-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl)aniline (100mg, 0.29 mmol). The resulting solution was stirred overnight at roomtemperature, diluted with water (100 ml), and extracted withdichloromethane (3×50 ml). The organic fractions were combined, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was purified by HPLC to affordN¹-[2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]-N²-[[5-(trifluoromethyl)-2,3-dihydro-1-benzofuran-2-yl]methyl]ethanediamideas a yellow solid (52 mg, 29%). (ES, m/z): [M+H]⁺ 619.10; ¹H NMR (300MHz, CDCl₃): δ 8.02 (d, J=9.3 Hz, 1H), 7.80 (br s, 1H), 7.72 (br s, 1H),7.41 (m, 2H), 6.84 (m, 2H), 6.63 (dd, J=9.0, 2.4 Hz, 1H), 5.00 (m, 1H),3.78 (m, 1H), 3.60-3.55 (m, 3H), 3.53-3.50 (m, 2H), 3.35 (br m, 3H),2.98 (dd, J=16.2, 7.2 Hz, 1H), 2.12 (m, 4H), 1.46-1.34 (m, 2H),1.29-1.22 (m, 2H).

Compound 220:N¹-(benzofuran-2-ylmethyl)-N²-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethyl)oxalamide

(ES, m/z): [M+H]⁺ 549.35; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.85 (br s, 1H), 7.75 (br s, 1H), 07.52 (d, J=6.6 Hz, 1H), 7.45 (d,J=8.4 Hz, 1H), 7.28-7.20 (m, 3H), 6.84 (s, 1H), 6.66 (s, 1H), 6.62 (d,J=2.4 Hz, 1H), 4.65 (d, J=6.0 Hz, 2H), 3.59 (m, 2H), 3.51 (m, 2H), 3.36(br m, 2H), 2.11 (m, 4H), 1.49-1.38 (m, 2H), 1.33-1.25 (m, 2H).

Compound 221:N¹-((5-fluorobenzofuran-2-yl)methyl)-N²-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethyl)oxalamide

(ES, m/z): [M+H]⁺ 567.00; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J=8.4 Hz,1H), 7.89 (br s, 1H), 7.74 (br s, 1H), 7.36 (dd, J=8.8, 4.0 Hz, 1H),7.17 (dd, J=8.4, 2.4 Hz, 1H), 6.98 (td, J=9.2, 2.8 Hz, 1H), 6.84 (d,J=2.0 Hz, 1H), 6.65 (overlapping signals, 2H), 4.64 (d, J=6.4 Hz, 2H),3.60-3.49 (m, 4H), 3.42-3.30 (m, 2H), 2.15-2.06 (m, 4H), 1.45-1.39 (m,2H), 1.32-1.23 (m, 2H).

Example 33 Preparation of Compound 222

Steps 1-3

The formation of 5-chloro-2-(chloromethyl)-1-benzofuran is described inthe synthesis of compound 184.

Step 4. Formation of 2-(azidomethyl)-5-chloro-1-benzofuran

To a solution of 5-chloro-2-(chloromethyl)-1-benzofuran (500 mg, 2.49mmol) in N,N-di methylformamide (10 ml) was added NaN₃ (320 mg, 4.92mmol) and the contents were stirred overnight at 70° C. The resultingsolution was diluted with saturated aqueous sodium bicarbonate (150 ml)and extracted with dichloromethane (3×70 ml). The organic layers werecombined, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum. The residue was purified by silica gel columnchromatography eluting with petroleum ether to afford2-(azidomethyl)-5-chloro-1-benzofuran as light brown oil (500 mg, 97%).¹H NMR (300 MHz, CDCl₃): δ 7.54 (s, 1H), 7.40 (d, J=9.0 Hz, 1H), 7.25(d, J=9.0 Hz, 1H), 6.66 (s, 1H), 4.50 (s, 2H).

Step 5. Formation of (5-chloro-1-benzofuran-2-yl)methanamine

To a solution of 2-(azidomethyl)-5-chloro-1-benzofuran (500 mg, 2.44mmol) in tetrahydrofuran (10 ml) and water (1 ml) was added PPh₃ (759mg, 2.89 mmol) and the contents were stirred for 3 hours at 60° C. Theresulting mixture was concentrated under vacuum to give a residue, whichwas purified by silica gel column chromatography eluting with methanolin dichloromethane to afford (5-chloro-1-benzofuran-2-yl)methanamine asa colorless liquid (420 mg, crude). (ES, m/z): [M+H]⁺ 182.0; ¹H NMR (400MHz, CDCl₃): δ 7.55-7.58 (m, 1H), 7.50-7.47 (m, 1H), 7.21 (d, J=8.8 Hz,1H), 6.50 (s, 1H), 3.99 (s, 2H).

Step 6. Formation of ethyl[[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate

To a solution of (5-chloro-1-benzofuran-2-yl)methanamine (420 mg, crude)in dichloromethane (50 ml) was added triethylamine (315 mg, 3.12 mmol).Then ethyl 2-chloro-2-oxoacetate (378 mg, 2.77 mmol) was added dropwiseand the contents were stirred for 30 minutes at 0° C. The resultingsolution was quenched with water (100 ml) and extracted withdichloromethane (3×70 ml). The organic fractions were combined, driedover anhydrous sodium sulfate, filtered, and concentrated under vacuum.The residue was purified by silica gel column chromatography elutingwith 20% ethyl acetate in petroleum ether to afford ethyl[[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate as an off-whitesolid (600 mg).

(ES, m/z): [M+H]⁺ 282.0; ¹H NMR (400 MHz, CDCl₃): δ 7.52 (s, 2H), 7.38(d, J=8.4 Hz, 1H), 7.26 (d, J=8.8 Hz, 1H), 6.64 (s, 1H), 4.68 (d, J=4.2Hz, 2H), 4.39 (q, J=7.2 Hz, 2H), 1.37 (t, J=7.2 Hz, 3H).

Step 7. Formation of lithio[[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate

To a solution of ethyl[[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate (200 mg, 0.71mmol) in methanol (5 ml) and water (0.1 ml) was added lithium hydroxidemonohydrate (20 mg, 0.84 mmol) and the contents were stirred for 30minutes at room temperature. The resulting mixture was concentratedunder vacuum to afford lithio[[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate as a white solid(160 mg, crude). ¹H NMR (300 MHz, DMSO-d6): δ 8.88 (s, 1H), 7.62 (s,1H), 7.53 (d, J=8.7 Hz, 1H), 7.26 (d, J=8.7 Hz, 1H), 6.66 (s, 1H), 4.37(s, 2H).

Step 8. Formation ofN¹-[(5-chloro-1-benzofuran-2-yl)methyl]-N²-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]ethanediamide(#222)

To a solution of lithio[[(5-chloro-1-benzofuran-2-yl)methyl]carbamoyl]formate (148 mg, 0.57mmol) in N,N-dimethylformamide (10 ml) was added EDAC.HCl (166 mg, 0.87mmol), HOBt (58.3 mg, 0.43 mmol), and triethylamine (87.3 mg, 0.86mmol). The solution was stirred for 1 hour at room temperature beforethe addition of N-[4-(2-aminoethoxy)cyclohexyl]-4-nitro-3-(trifluoromethyl)aniline (100 mg, 0.29 mmol). Thecontents were then stirred overnight at room temperature. The resultingsolution was quenched with water (100 ml) and extracted withdichloromethane (3×60 ml). The organic layers were combined, dried overanhydrous sodium sulfate, filtered, and concentrated under vacuum togive a residue, which was purified by HPLC to affordN¹-[(5-chloro-1-benzofuran-2-yl)methyl]-N²-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethyl]ethanediamideas a yellow solid (41 mg, 24%). (ES, m/z): [M+H]⁺ 583.20; ¹H NMR (400MHz, CDCl₃): δ 8.02 (d, J=7.6 Hz, 1H), 7.85 (br s, 1H), 7.73 (br s, 1H),7.49 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.23 (m, 1H), 6.84 (s, 1H), 6.63(d, J=8.4 Hz, 1H), 6.60 (s, 1H), 4.64 (d, J=6.0 Hz, 2H), 3.58 (m, 2H),3.52 (m, 2H), 3.41-3.30 (m, 2H), 2.10 (m, 4H), 1.48-1.42 (m, 2H),1.29-1.23 (m, 2H).

N¹-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethyl)-N²-((5-(trifluoromethyl) benzofuran-2-yl)methyl)oxalamide (#223)

(ES, m/z): [M+H]⁺ 617.25; ¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J=9.2 Hz,1H), 7.91 (br s, 1H), 7.83 (s, 1H), 7.76 (br s, 1H), □7.54 (s, 2H), 6.84(s, 1H), 6.73 (s, 1H), 6.64-6.62 (dd, J=1.6, 8.8 Hz, 1H), 4.68 (d, J=6.0Hz, 2H), 3.61-3.52 (m, 4H), 3.40-3.33 (m, 2H), 2.16-2.08 (m, 4H),1.46-1.43 (m, 2H), 1.29-1.26 (m, 2H).

N¹-((2,3-dihydrobenzofuran-2-yl)methyl)-N²-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)phenoxy)ethyl)oxalamide (#224).

(ES, m/z): [M+H]⁺ 545.25; ¹H NMR (300 MHz, CDCl₃): δ 7.98 (d, J=9.0 Hz,1H), 7.82 (d, J=5.4 Hz, 2H), 7.17-7.10 (m, 5H), 6.97-6.78 (m, 5H), 6.19(br s, 1H), 4.95-4.86 (m, 1H), 4.10 (t, J=5.1 Hz, 2H), 3.81-3.73 (m,3H), 3.54-3.49 (m, 1H), 3.36-3.28 (m, 1H), 2.96-2.89 (m, 1H).

Compound 225:N¹-((5-fluoro-2,3-dihydrobenzofuran-2-yl)methyl)-N²-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)phenoxy)ethyl)oxalamide

(ES, m/z): [M+H]⁺ 563.25; ¹H NMR (300 MHz, CDCl₃): δ 8.00 (d, J=9.3 Hz,1H), 7.96-7.80 (m, 2H), □7.14 (d, J=9.0 Hz, 2H), 7.10 (s, 1H), 6.96-6.77(m, 5H), 6.69 (dd, J=8.7, 4.2 Hz, 1H), 6.19 (br s, 1H), 4.94-4.88 (m,1H), 4.11 (t, J=5.1 Hz, 2H), 3.76 (t, J=5.4 Hz, 2H), 3.72-3.69 (m, 1H),3.55-3.48 (m, 1H), 3.29-3.26 (m, 1H), 2.90 (dd, J=16.2, 7.2 Hz, 1H).

Compound 226:N¹-((5-chloro-2,3-dihydrobenzofuran-2-yl)methyl)-N²-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)phenoxy)ethyl)oxalamide

(ES, m/z): [M+H]⁺ 579.20; ¹H NMR (400 MHz, CDCl₃): δ 7.97 (d, J=8.8 Hz,1H), 7.80 (d, J=8.8 Hz, 2H), □7.16-7.07 (m, 5H), 6.95 (d, J=8.4 Hz, 2H),6.89 (d, J=8.4 Hz, 1H), 6.70 (d, J=8.4 Hz, 1H), 6.18 (br s, 1H),4.94-4.92 (m, 1H), 4.11 (d, J=4.4 Hz, 2H), 3.78-3.71 (m, 3H), 3.54-3.47(m, 1H), 3.33-3.27 (m, 1H), 2.94-2.88 (m, 1H).

Compound 227:N¹-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)phenoxy)ethyl)-N²-((5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl)methyl)ethanediamide

(ES, m/z): [M+H]⁺ 613.25; ¹H NMR (300 MHz, CDCl₃): δ 8.01 (d, J=9.0 Hz,1H), 7.93 (br s, 2H), 7.51 (s, 2H), 7.20-7.13 (m, 3H), 6.99-6.82 (m,4H), 6.22 (s, 1H), 5.04-5.02 (m, 1H), 4.15-4.12 (m, 2H), 3.93-3.77 (m,3H), 3.60-3.52 (m, 1H), 3.44-3.36 (m, 1H), 3.08-2.96 (m, 1H).

Compound 228:N¹-(benzofuran-2-ylmethyl)-N²-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)phenoxy)ethyl)oxalamide

(ES, m/z): [M+H]⁺ 543.50; ¹H NMR (300 MHz, CDCl₃): δ 7.96 (d, J=9.0 Hz,1H), 7.86 (br s, 2H), □7.52 (d, J=7.2 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H),7.31-7.09 (m, 5H), 6.96-6.88 (m, 3H), 6.66 (s, 1H), 6.20 (br s, 1H),4.66 (d, J=6.0 Hz, 2H), 4.10 (t, J=5.1 Hz, 2H), 3.78 (t, J=5.4 Hz, 2H).

Compound 229:N¹-((5-fluorobenzofuran-2-yl)methyl)-N²-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)phenoxy)ethyl)oxalamide

(ES, m/z): [M−H]⁻ 559.25; ¹H NMR (400 MHz, CDCl₃): δ 7.97 (d, J=9.2 Hz,1H), 7.88 (s, 2H), 7.38 (d, J=4.0 Hz, 1H), 7.19-7.09 (m, 4H), 7.02-6.87(m, 4H), 6.63 (s, 1H), 4.64 (d, J=6.4 Hz, 2H), 4.10 (t, J=5.2 Hz, 2H),3.77 (m, 2H).

Compound 230:N¹-((5-chlorobenzofuran-2-yl)methyl)-N²-(2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)phenoxy)ethyl)oxalamide

(ES, m/z): [M−H]⁻ 575.29; ¹H NMR (400 MHz, CDCl₃): δ 8.02 (d, J=8.4 Hz,1H), 7.99 (s, 2H), □7.52 (s, 1H), 7.36 (d, J=8.8 Hz, 1H), 7.26-7.22 (m,1H), 7.16-7.10 (m, 3H), 6.96-6.88 (m, 3H), 6.61 (s, 1H), 6.17 (br s,1H), 4.64 (d, J=5.6 Hz, 2H), 4.10 (t, J=4.8 Hz, 2H), 3.77 (m, 2H).

Example 34 Preparation of Compound 231

Steps 1-7

The formation of[4-(2-amino-ethoxy)-phenyl]-(4-nitro-3-trifluoromethyl-phenyl)-amine wasperformed in a manner analogous to what is described in the synthesis ofcompound 224 and the formation of lithium2-((5-trifluoromethylbenzofuran-2-yl)methylamino)-2-oxoacetate wasperformed in a manner analogous to what is described in the synthesis ofcompound 223.

Step 8. Formation ofN¹-[2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)ethyl]-N²-[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]ethanediamide(#231)

The mixture of lithio([[5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]carbamoyl)formate (130mg, crude), EDAC.HCl (166 mg, 0.87 mmol), HOBt (58.3 mg, 0.43 mmol), andtriethylamine (87.3 mg, 0.86 mmol) in N,N-dimethylformamide (10 ml) wasstirred for 1 hour at room temperature before the addition ofN-[4-(2-aminoethoxy)phenyl]-4-nitro-3-(trifluoromethyl)aniline (100 mg,0.29 mmol). The resulting solution was stirred overnight at roomtemperature and then quenched by the addition of water (100 ml) andextracted with dichloromethane (3×20 ml). The organic layers werecombined, dried over sodium sulfate, filtered, and concentrated undervacuum to give a residue, which was purified by Prep-HPLC to affordN¹-[2-(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]phenoxy)ethyl]-N²45-(trifluoromethyl)-1-benzofuran-2-yl]methyl]ethanediamideas a yellow solid (9.3 mg, 5%).

(ES, m/z): [M−H]⁻ 609.25; ¹H NMR (300 MHz, CDCl₃): δ 8.01 (d, J=9.0 Hz,1H), 7.90 (br s, 2H), 7.87 (s, 1H), 7.57 (s, 2H), 7.19-7.12 (m, 3H),7.00-6.90 (m, 3H), 6.76 (s, 1H), 6.20 (s, 1H), 4.71 (d, J=6.0 Hz, 2H),4.14 (t, J=5.1 Hz, 2H), 3.81 (m, 2H).

Compound 234:1-[4-[(5-fluoro-1-benzothiophen-2-yl)methyl]piperazin-1-yl]-2-[[4-[[4-nitro-3-(trifluorometh-yl)phenyl]amino]cyclohexyl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 595.00; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J=9.2 Hz,1H), 7.70 (br s, 1H), 7.36 (s, 1H), 7.18-7.02 (m, 2H), 6.84 (d, J=2.0Hz, 1H), 6.62 (dd, J=9.2, 2.4 Hz, 1H), 4.42 (m, 1H), 4.18 (s, 2H), 3.81(s, 2H), 3.68-3.52 (overlapping m, 4H), 3.40 (m, 2H), 2.55 (m, 3H), 2.2(m, 4H), 1.54 (m, 2H), 1.26 (m, 2H).

Compound 236:1-(4-(5-fluorobenzo[b]thiophen-2-yl)piperazin-1-yl)-2-((4-((4-nitro-3-(trifluoromethyl)phenyl)amino)cyclohexyl)oxy)ethanone

(ES, m/z): [M+H]⁺ 581.00; ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J=9.0 Hz,1H), 7.71 (dd, J=5.1, 8.7 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.25 (dd,J=2.4, 10.2 Hz, 1H), 7.07 (s, 1H), 6.93-6.83 (m, 2H), 6.35 (s, 1H), 4.21(s, 2H), 3.62-3.55 (m, 4H), 3.48-3.24 (m, 6H), 2.05-1.94 (m, 4H),1.43-1.18 (m, 4H).

1-[4-(5-fluoro-1,3-benzothiazol-2-yl)piperazin-1-yl]-2-[[4-[[4-nitro-3-(trifluoromethyl)pheny-1]amino]cyclohexyl]oxy]ethan-1-one(#237)

(ES, m/z): [M+H]⁺ 582.05; ¹H NMR (400 MHz, CDCl₃): δ 8.01 (d, J=9.2 Hz,1H), 7.52 (dd, J=8.8, 5.6 Hz, 1H), 7.28-7.25 (m, 1H), 6.89-6.84 (m, 2H),6.63 (dd, J=9.2, 2.8 Hz, 1H), 4.47 (m, 1H), 4.24 (s, 2H), 3.75 (m, 6H),3.64 (m, 2H), 3.45 (m, 2H), 2.12 (m, 4H), 1.47 (m, 2H), 1.29 (m, 2H).

Compound 247:1-(4-(6-fluoroquinolin-2-yl)piperazin-1-yl)-2-(4-(methyl(4-nitro-3-(trifluoromethyl)phenyl)amino)cyclohexyloxy)ethanone

(ES, m/z): [M+H]⁺ 589.95; ¹H NMR (300 MHz, CD₃OD): δ 8.05-8.00 (m, 2H),7.71-7.68 (m, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 1H),7.08-7.01 (m, 2H), 4.34 (s, 2H), 3.88-3.71 (m, 9H), 3.50-3.32 (m, 1H),2.95 (s, 3H), 2.27-2.23 (m, 2H), 1.85-1.71 (m, 4H), 1.60-1.47 (m, 2H).

Compound 248:1-(4-(6-fluoronaphthalen-2-yl)piperazin-1-yl)-2-(4-(methyl(4-nitro-3-(trifluoromethyl)phenyl)amino)cyclohexyloxy)ethanone

(ES, m/z): [M+H]⁺ 589.15; ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J=9.3 Hz,1H), 7.75-7.69 (m, 2H), 7.41-7.21 (m, 4H), 6.98 (s, 1H), 6.77 (dd,J=9.3, 3.0 Hz, 1H), 4.28 (s, 2H), 3.90-3.85 (m, 4H), 3.74-3.71 (m, 1H),3.45-3.40 (m, 1H), 3.32-3.31 (m, 4H), 2.90 (s, 3H), 2.28-2.24 (m, 2H),1.90-1.84 (m, 2H), 1.70-1.46 (m, 4H).

Compound 253:1-(4-[[3-chloro-5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 663.30; ¹H NMR (300 MHz, CD₃OD): δ 8.03 (d, J=9.0 Hz,1H), 7.91 (s, 1H), 7.74 (m, 2H), 6.98 (d, J=2.7 Hz, 1H), 6.77 (dd,J=9.0, 2.7 Hz, 1H), 4.24 (s, 2H), 3.92 (s, 2H), 3.62 (m, 4H), 3.41 (m,2H), 2.65 (m, 4H), 2.09 (m, 4H), 1.54-1.2 (m, 4H).

Compound 254:2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]-1-(4-[1-[5-(trifluoromethyl)-1-benzofuran-2-yl]ethyl]piperazin-1-yl)ethan-1-one

(ES, m/z): [M+H]⁺ 643.30; ¹H NMR (300 MHz, DMSO-d6): δ 8.07-8.02(overlapping d, 2H), 7.78 (d, J=8.7 Hz, 1H), 7.58 (dd, J=9.0, 1.5 Hz,1H), 7.41 (d, J=7.8 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H), 6.90 (s, 1H), 6.82(dd, J=9.3, 2.4 Hz, 1H), 4.08 (m, 3H), 3.42 (m, 5H), 3.27 (m, 1H), 2.50(s, 2H), 2.40 (m, 2H), 1.90 (m, 4H), 1.45 (d, J=7.2 Hz, 3H), 1.34-1.23(m, 5H).

Compound 255:2-1-(4-[1-[3-chloro-5-(trifluoromethyl)-1-benzofuran-2-yl]ethyl]piperazin-1-yl)-2-[[4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 677.10; ¹H NMR (300 MHz, CD₃OD): δ 7.98 (d, J=9.0 Hz,1H), 7.93 (s, 1H), 7.75 (m, 2H), 6.92 (d, J=2.4 Hz, 1H), 6.71 (dd,J=9.0, 2.4 Hz, 1H), 4.72 (br s, 1H), 4.17 (s, 2H), 3.69 (br s, 4H), 3.32(m, 2H), 3.00 (br m, 4H), 1.98 (m, 4H), 1.72 (d, J=6.3 Hz, 3H), 1.30 (broverlapping m, 4H).

Compound 256:2-[[4-[methyl]4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]-1-(4-[[5-(trifluorom-ethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)ethan-1-one

(ES, m/z): [M+H]⁺ 643.10; ¹H NMR (300 MHz, CD₃OD): δ 7.95 (d, J=9.3 Hz,1H), 7.81 (s, 1H), 7.52 (d, J=8.7 Hz, 1H), 7.45 (d, J=8.4 Hz, 1H), 6.92(m, 2H), 6.77 (s, 1H), 4.12 (s, 2H), 3.73 (s, 3H), 3.49 (m, 4H), 3.25(m, 1H), 2.81 (s, 3H), 2.52 (m, 4H), 2.06 (m, 2H), 1.69-1.43 (m, 4H),1.41-1.29 (m, 2H).

Compound 257:2-[[4-[methyl]4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]-1-(4-[1-[5-(trifluoro-methyl)-1-benzofuran-2-yl]ethyl]piperazin-1-yl)ethan-1-one

(ES, m/z): [M+H]⁺ 657.15; ¹H NMR (300 MHz, DMSO-d6): δ 8.06 (d, J=9.0Hz, 1H), 8.02 (s, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.57 (dd, J=8.7, 1.8 Hz,1H), 7.08 (overlapping s & d, 2H), 6.90 (s, 1H), 4.05 (overlapping s &m, 3H), 3.87 (m, 1H), 3.45 (m, 4H), 3.23 (m, 1H), 2.85 (s, 3H), 2.50 (m,2H), 2.38 (m, 2H), 1.97 (m, 2H), 1.55 (m, 4H), 1.45 (d, J=6.9 Hz, 3H),1.38 (m, 2H).

Compound 258:1-(4-[[3-chloro-5-(trifluoromethyl)-1-benzofuran-2-yl]methyl]piperazin-1-yl)-2-[[4-[methyl]4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 677.25; ¹H NMR (300 MHz, CDCl₃) δ 8.06 (d, J=9.3 Hz,1H), 7.88 (s, 1H), 7.60 (m, 2H), 6.98 (d, J=1.5 Hz, 1H), 6.76 (dd,J=6.6, 3.0 Hz, 1H), 4.17 (s, 2H), 3.85 (br s, 2H), 3.66 (m, 4H), 3.35(m, 2H), 2.87 (s, 3H), 2.62 (m, 4H), 2.19 (m, 2H), 1.80 (m, 2H),1.65-1.35 (overlapping m, 4H).

Compound 259:1-(4-[1-[3-chloro-5-(trifluoromethyl)-1-benzofuran-2-yl]ethyl]piperazin-1-yl)-2-[[4-[methyl-[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 691.10; ¹H NMR (300 MHz, DMSO-d6): δ 8.07 (d, J=9.0Hz, 1H), 7.92-7.88 (m, 2H), 7.74 (d, J=1.2, 9.0 Hz, 1H), 7.06(overlapping s & d, 2H), 4.15 (q, J=7.2 Hz, 1H), 4.08 (s, 2H), 3.84 (m,1H), 3.42 (m, 4H), 3.20 (m, 1H), 2.83 (s, 3H), 2.50 (br m, 4H), 1.95 (m,2H), 1.51 (d, J=6.9 Hz, 3H), 1.50-1.21 (m, 6H).

Compounds 262 & 262-10:1-(4-((S)-1-((R)-5-fluoro-2,3-dihydrobenzofuran-2-yl)ethyl)piperazin-1-yl)-2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethanone &1-(4-((S)-1-((S)-5-fluoro-2,3-dihydrobenzofuran-2-yl)ethyl)piperazin-1-yl)-2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethanone

(E/S, m/z): [M+H]⁺ 595.10; ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J=9.3 Hz,1H), 6.99 (d, J=2.4 Hz, 1H), 6.87 (d, J=7.8 Hz, 1H), 6.78 (m, 2H), 6.65(dd, J=4.2, 8.7 Hz, 1H), 4.80 (br m, 1H), 4.21 (s, 2H), 3.80-3.50(overlapping m, 5H), 3.40 (m, 1H), 3.32-3.08 (m, 4H), 2.90 (s, 3H),2.78-2.48 (overlapping m, 4H), 2.24 (m, 2H), 1.85 (m, 2H), 1.70-1.40 (m,4H), 1.10 (d, J=5.1 Hz, 3H).

(ES, m/z): [M+H]⁺ 609.20; ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J=9.3 Hz,1H), 6.99 (d, J=2.4 Hz, 1H), 6.88 (d, J=7.2 Hz, 1H), 6.76 (dd, J=3.0,9.3 Hz, 2H), 6.63 (m, 1H), 4.80 (br m, 1H), 4.19 (s, 2H), 3.72 (m, 1H),3.65-3.34 (overlapping m, 6H), 3.14 (apparent d, J=9.0 Hz, 2H), 2.90 (s,3H), 2.85 (m, 1H), 2.69 (m, 3H), 2.23 (m, 2H), 1.84 (m, 2H), 1.72-1.39(overlapping m, 4H), 1.12 (d, J=Hz, 3H).

Relative stereochemical assignments are tentative.

Compounds 260 & 260-10:1-(4-((S)-1-((R)-5-fluoro-2,3-dihydrobenzofuran-2-yl)ethyl)piperazin-1-yl)-2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethanone &1-(4-((S)-1-((S)-5-fluoro-2,3-dihydrobenzofuran-2-yl)ethyl)piperazin-1-yl)-2-(4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethanone

(E/S, m/z): [M+H]⁺ 595.10; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 6.88 (m, 2H), 6.79 (dd, J=8.4, 9.6 Hz, 1H), 6.65 (m, 2H), 4.82 (brs, 1H), 4.46 (d, J=7.5 Hz, 1H), 4.20 (s, 2H), 3.75-3.10 (m, 8H),2.80-2.45 (m, 4H), 2.14 (m, 4H), 1.50 (m, 2H), 1.30 (m, 2H), 1.10-1.08(d, J=9.0 Hz, 3H).

(E/S, m/z): [M+H]⁺ 595.10; ¹H NMR (300 MHz, CDCl₃): δ 8.03 (d, J=9.0 Hz,1H), 6.88 (m, 2H), 6.79 (m, 1H), 6.64 (m, 2H), 4.80 (br s, 1H), 4.46 (d,J=7.8 Hz, 1H), 4.19 (s, 2H), 3.69-3.32 (br m, 6H), 3.13 (m, 2H), 2.86(m, 1H), 2.67 (br s, 3H), 2.14 (m, 4H), 1.46 (m, 2H), 1.28 (m, 2H), 1.12(d, J=6.0 Hz, 3H).

Relative stereochemical assignments are tentative.

Compound 266:2-[[4-[(4-nitro-3-trifluoromethyl-phenyl)amino]cyclohexyl]oxy]-1-[4-(6-bromoquinolin-2-yl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 636; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (dd, J=9.2 Hz,2.0 Hz, 1H), 7.97 (d, J=2.3 Hz, 1H), 7.63 (dd, J=8.9 Hz, 2.3 Hz, 1H),7.51 (d, J=8.9 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.32 (d, J=9.3 Hz, 1H),7.07 (s, 1H), 6.85 (dd, J=9.7 Hz, 2.4 Hz, 1H), 4.22 (s, 2H), 3.80-3.68(m, 4H), 3.62-3.54 (m, 4H), 3.52-3.43 (m, 1H), 3.42-3.34 (m, 1H),2.09-1.91 (m, 4H), 1.45-1.18 (m, 4H).

Compound 269:2-[(4-[methyl-[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(6-bromoquinolin-2-yl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 650; ¹H NMR (400 MHz, DMSO-d6): δ 8.06 (dd, J=9.2 Hz,3.0 Hz, 2H), 7.97 (d, J=2.2 Hz, 1H), 7.63 (dd, J=8.9 Hz, 2.3 Hz, 1H),7.51 (d, J=8.9 Hz, 1H), 7.33 (d, J=9.2 Hz, 1H), 7.14-7.05 (m, 2H), 4.23(s, 2H), 3.99-3.90 (m, 1H), 3.81-3.68 (m, 4H), 3.63-3.55 (m, 4H),3.42-3.34 (m, 1H), 2.90 (s, 3H), 2.16-2.06 (m, 2H), 1.72-1.56 (m, 4H),1.52-1.38 (m, 2H).

Compound 245:2-[[(1r,4r)-4-[methyl[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one

(ES, m/z): [M+H]⁺ 640.35; ¹H NMR (300 MHz, CD₃OD): δ 8.16 (d, J=9.3 Hz,1H), 8.09 (d, J=9.3 Hz, 1H), 8.05 (s, 1H), 7.76 (m, 2H), 7.33 (d, J=9.3Hz, 1H), 7.09 (m, 2H), 4.37 (s, 2H), 3.92 (overlapping m, 5H), 3.77 (m,4H), 3.49 (br m, 1H), 2.97 (s, 3H), 2.27 (m, 2H), 1.90-1.70 (m, 4H),1.62-1.48 (m, 2H).

Compound 246:1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]-2-[[4-[methyl]4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl]oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 606.30; ¹H NMR (400 MHz, CDCl₃): δ 8.05 (d, J=9.6 Hz,1H), 7.87 (s, 1H), 7.70-7.35 (overlapping m, 3H), 7.00 (d, J=8.8 Hz,1H), 6.98 (d, J=2.4 Hz, 1H), 6.77 (dd, J=2.8, 9.2 Hz, 1H), 4.27 (s, 2H),3.94-3.68 (overlapping m, 9H), 3.42 (m, 1H), 2.90 (s, 3H), 2.28 (m, 2H),1.85 (m, 2H), 1.69-1.40 (m, 4H).

Compound 247:1-(4-(6-fluoroquinolin-2-yl)piperazin-1-yl)-2-(4-(methyl(4-nitro-3-(trifluoromethyl)phenyl)amino)cyclohexyloxy)ethanone

(ES, m/z): [M+H]⁺ 589.95; ¹H NMR (300 MHz, CD₃OD): δ 8.05-8.00 (m, 2H),7.71-7.68 (m, 1H), 7.37 (d, J=9.0 Hz, 2H), 7.25 (d, J=9.0 Hz, 1H),7.08-7.01 (m, 2H), 4.34 (s, 2H), 3.88-3.71 (m, 9H), 3.50-3.32 (m, 1H),2.95 (s, 3H), 2.27-2.23 (m, 2H), 1.85-1.71 (m, 4H), 1.60-1.47 (m, 2H).

Compound 248:1-(4-(6-fluoronaphthalen-2-yl)piperazin-1-yl)-2-(4-(methyl(4-nitro-3-(trifluoromethyl)phenyl)amino)cyclohexyloxy)ethanone

(ES, m/z): [M+H]⁺ 589.15; ¹H NMR (300 MHz, CDCl₃): δ 8.05 (d, J=9.3 Hz,1H), 7.73 (overlapping m, 2H), 7.41-7.21 (overlapping m, 4H), 6.98 (s,1H), 6.77 (dd, J=9.3, 3.0 Hz, 1H), 4.28 (s, 2H), 3.88 (m, 4H), 3.73 (m,1H), 3.43 (m, 1H), 3.32 (m, 4H), 2.90 (s, 3H), 2.26 (m, 2H), 1.84 (m,2H), 1.72 (m, 2H), 1.48 (m, 2H).

Compound 178:1-[4-[(5-chloro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 594.95; ¹H NMR (400 MHz, CDCl₃): δ 8.04 (d, J=9.2 Hz,1H), 7.51 (s, 1H), 7.41 (d, J=8.8 Hz, 1H), 7.19-7.26 (m, 1H), 6.84 (s,1H), 6.63 (m, 2H), 4.44 (d, J=7.2 Hz, 1H), 4.18 (s, 2H), 3.51-3.85 (m,6H), 3.39-3.42 (m, 2H), 2.56 (br s, 4H), 2.03-2.14 (m, 4H), 1.41-1.59(m, 2H), 1.12-1.28 (m, 2H).

Compound 274:2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5-chlorobenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 575; ¹H NMR (400 MHz, DMSO-d6): δ 7.69 (d, J=8.8 Hz,1H), 7.66 (d, J=2.3 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.28 (dd, J=8.7 Hz,2.2 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.01 (s, 1H), 6.84 (dd, J=8.7 Hz,2.2 Hz, 1H), 6.79 (s, 1H), 4.11 (s, 2H), 3.72 (s, 2H) 3.49-3.26 (m, 6H),2.52-2.40 (m, 4H), 2.02-1.86 (m, 4H), 1.39-1.25 (m, 2H), 1.23-1.11 (m,2H).

Compound 275:2-[(4-[methyl]4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5-chlorobenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 609; ¹H NMR (400 MHz, DMSO-d6): δ 8.07 (d, J=9.2 Hz,1H), 7.67 (d, J=2.2 Hz, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.28 (dd, J=8.7 Hz,2.2 Hz, 1H), 7.12-7.05 (m, 2H), 6.80 (s, 1H), 4.12 (s, 2H), 3.96-3.87(m, 1H), 3.73 (s, 2H), 3.50-3.40 (m, 4H), 3.34-3.25 (m, 1H), 2.89 (s,3H), 2.53-2.40 (m, 4H), 2.08-1.99 (m, 2H), 1.69-1.53 (m, 4H), 1.46-1.33(m, 2H).

Compound 271:2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-(6-bromoquinolin-2-yl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 616; ¹H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J=9.2 Hz,1H), 7.97 (d, J=2.3 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.63 (dd, J=8.9 Hz,2.3 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.32 (d, J=9.3 Hz, 1H), 7.10 (d,J=7.8 Hz, 1H), 7.01 (s, 1H), 6.85 (dd, J=8.7 Hz, 2.2 Hz, 1H), 4.21 (s,2H), 3.79-3.68 (m, 4H), 3.62-3.55 (m, 4H), 3.47-3.32 (m, 2H), 2.07-2.00(m, 2H), 1.98-1.90 (m, 2H), 1.43-1.31 (m, 2H), 1.28-1.16 (m, 2H).

Compound 272:2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-(6-chloroquinolin-2-yl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 572; ¹H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J=9.2 Hz,1H), 7.83 (d, J=2.4 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.58 (d, J=9.0 Hz,1H), 7.52 (dd, J=8.9 Hz, 2.4 Hz, 1H), 7.33 (d, J=9.3 Hz, 1H), 7.10 (d,J=7.8 Hz, 1H), 7.01 (s, 1H), 6.85 (dd, J=8.7 Hz, 2.3 Hz, 1H), 4.21 (s,2H), 3.79-3.68 (m, 4H), 3.62-3.54 (m, 4H), 3.47-3.32 (m, 2H), 2.08-2.00(m, 2H), 1.98-1.90 (m, 2H), 1.44-1.31 (m, 2H), 1.28-1.16 (m, 2H).

Compound 273:2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 606; ¹H NMR (400 MHz, DMSO-d6): δ 8.23 (d, J=9.3 Hz,1H), 8.17 (s, 1H), 7.66 (dd, J=8.9 Hz, 2.1 Hz, 1H), 7.72-7.66 (m, 3H),7.39 (d, J=9.3 Hz, 1H), 7.10 (d, J=7.8 Hz, 1H), 7.01 (s, 1H), 6.85 (dd,J=8.7 Hz, 2.2 Hz, 1H), 4.22 (s, 2H), 3.86-3.75 (m, 4H), 3.63-3.56 (m,4H), 3.47-3.32 (m, 2H), 2.08-2.00 (m, 2H), 1.98-1.90 (m, 2H), 1.44-1.31(m, 2H), 1.28-1.16 (m, 2H).

Compound 281:2-[(4-[methyl[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]-1-[4-(6-bromoquinolin-2-yl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 630; ¹H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J=9.2 Hz,1H), 7.97 (d, J=2.2 Hz, 1H), 7.76 (d, J=8.8 Hz, 1H), 7.63 (dd, J=8.9 Hz,2.3 Hz, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.33 (d, J=9.3 Hz, 1H), 7.13-7.07(m, 2H), 4.22 (s, 2H), 3.94-3.84 (m, 1H), 3.79-3.69 (m, 4H), 3.63-3.55(m, 4H), 3.41-3.32 (m, 1H), 2.85 (s, 3H), 2.14-2.05 (m, 2H), 1.69-1.55(m, 4H), 1.51-1.38 (m, 2H).

Compound 282:2-[(4-[methyl]4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(6-chloroquinolin-2-yl)-piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 586; ¹H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J=9.3 Hz,1H), 7.83 (d, J=2.1 Hz, 1H), 7.76 (d, J=8.5 Hz, 1H), 7.6-7.50 (m, 2H),7.33 (d, J=9.2 Hz, 1H), 7.14-7.05 (m, 2H), 4.22 (s, 2H), 3.94-3.84 (m,1H), 3.81-3.68 (m, 4H), 3.63-3.55 (m, 4H), 3.41-3.32 (m, 1H), 2.85 (s,3H), 2.14-2.05 (m, 2H), 1.69-1.55 (m, 4H), 1.51-1.38 (m, 2H).

Example 35 Preparation of Compound 283

Compound 283 Formation of2-[(4-[methyl[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-[6-(trifluoromethyl)quinolin-2-yl]-piperazin-1-yl]ethan-1-one(#283)

To a solution of2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]-cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl]piperazin-1-yl]ethan-1-one(100 mg, 0.16 mmol) in THF (3 ml) was added sodium hydride (25 mg, 0.63mmol, 3.9 eq.) and the mixture was stirred for 30 minutes. The mixturewas then treated with iodomethane (100 mg, 0.7 mmol, 4 eq.) and stirredfor 5 days. The resulting mixture was diluted with water (30 ml), andextracted with ethyl acetate (30 mL). The organic layer was separated,washed with brine, dried over anhydrous sodium sulfate, filtered, andconcentrated under vacuum to give a residue from which the product waspurified by silica gel column flash chromatography eluting with ethylacetate/heptanes to afford2-[(4-[methyl]4-cyano-3-(trifluoromethyl)phenyl]-aminol-cyclohexyl)oxy]-1-[4-[6-(trifluoromethyl)quinolin-2-yl)piperazin-1-yl]ethan-1-oneas a yellow solid (100 mg, 98%). (CI, m/z): [M+H]⁺ 620; ¹H NMR (400 MHz,DMSO-d6): δ 8.24 (d, J=9.3 Hz, 1H), 8.17 (s, 1H), 7.76 (d, J=8.7 Hz,2H), 7.70 (d, J=8.7 Hz, 1H), 7.40 (d, J=9.3 Hz, 1H), 7.13-7.07 (m, 2H),4.23 (s, 2H), 3.94-3.76 (m, 5H), 3.63-3.57 (m, 4H), 3.41-3.32 (m, 1H),2.85 (s, 3H), 2.14-2.05 (m, 2H), 1.69-1.57 (m, 4H), 1.50-1.38 (m, 2H).

Compound 284:2-[(4-[methyl[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(6-chlorobenzofuran-2-ylmethyl)-piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 589 ¹H NMR (400 MHz, DMSO-d6): δ 7.76 (d, J=9.0 Hz,1H), 7.67 (s, 1H), 7.58 (d, J=8.7 Hz, 1H), 7.28 (d, J=8.5 Hz, 1H),7.12-7.04 (m, 2H), 6.79 (s, 1H), 4.12 (s, 2H), 3.91-3.80 (m, 1H), 3.73(s, 2H), 3.51-3.39 (m, 4H), 3.33-3.23 (m, 1H), 2.83 (s, 3H), 2.54-2.38(m, 4H), 2.07-1.97 (m, 2H), 1.66-1.49 (m, 4H), 1.46-1.31 (m, 2H).

Step 5. Formation of2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5-fluorobenzoxazol-2-ylmethyl)piperazin-1-yl]ethan-1-one(#285)

(CI, m/z): [M+H]⁺ 580; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.3 Hz,1H), 7.77 (dd, J=4.3 Hz, 9.4 Hz, 1H), 7.62 (dd, J=8.7 Hz, 2.6 Hz, 1H),7.43 (d, J=7.7 Hz, 1H), 7.26 (td, J=9.6 Hz, 2.6 Hz, 1H), 7.06 (s, 1H),6.84 (dd, J=9.3 Hz, 2.5 Hz, 1H), 4.12 (s, 2H), 3.92 (s, 2H), 3.51-3.38(m, 5H), 3.36-3.26 (m, 1H), 2.60-2.50 (m, 4H), 2.04-1.88 (m, 4H),1.40-1.15 (m, 4H).

Compound 286:2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5-fluorobenzoxazol-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 560; ¹H NMR (400 MHz, DMSO-d6): δ 7.77 (dd, J=4.3 Hz,9.0 Hz, 1H), 7.69 (d, J=8.7 Hz, 1H), 7.62 (dd, J=8.8 Hz, 2.6 Hz, 1H),7.26 (td, J=9.0 Hz, 2.6 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.01 (s, 1H),6.84 (dd, J=8.7 Hz, 2.2 Hz, 1H), 4.12 (s, 2H), 3.92 (s, 2H), 3.51-3.27(m, 6H), 2.60-2.50 (m, 4H), 2.02-1.86 (m, 4H), 1.38-1.26 (m, 2H),1.24-1.12 (m, 2H).

Compound 287:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5-chlorobenzoxazol-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 595; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.86 (d, J=2.1 Hz, 1H), 7.78 (d, J=8.7 Hz, 1H), 7.47-7.40 (m, 2H),7.06 (s, 1H), 6.84 (dd, J=9.3 Hz, 2.4 Hz, 1H), 4.12 (s, 2H), 3.93 (s,2H), 3.52-3.38 (m, 5H), 3.36-3.26 (m, 1H), 2.60-2.50 (m, 4H), 2.04-1.88(m, 4H), 1.40-1.15 (m, 4H).

Compound 288:2-[(4-[[4-cyano-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5-chlorobenzoxazol-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 576; ¹H NMR (400 MHz, DMSO-d6): δ 7.86 (d, J=2.1 Hz,1H), 7.77 (d, J=8.7 Hz, 1H), 7.69 (d, J=7.7 Hz, 1H), 7.44 (dd, J=8.7 Hz,2.3 Hz, 1H), 7.08 (d, J=7.8 Hz, 1H), 7.01 (s, 1H), 6.84 (dd, J=8.7 Hz,2.2 Hz, 1H), 4.12 (s, 2H), 3.93 (s, 2H), 3.50-3.26 (m, 6H), 2.60-2.50(m, 4H), 2.02-1.86 (m, 4H), 1.38-1.26 (m, 2H), 1.24-1.12 (m, 2H).

Compound 297:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(6-fluoronaphthalen-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 589; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.98 (dd, J=9.1 Hz, 5.9 Hz, 1H), 7.88 (d, J=8.5 Hz, 1H), 7.85 (s,1H), 7.68 (dd, J=10.4 Hz, 2.6 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.46-7.37(m, 2H), 7.06 (s, 1H), 6.84 (dd, J=9.3 Hz, 2.5 Hz, 1H), 4.12 (s, 2H),3.65 (s, 2H), 3.51-3.39 (m, 5H), 3.32-3.27 (m, 1H), 2.45-2.33 (m, 4H),2.04-1.88 (m, 4H), 1.41-1.14 (m, 4H).

Compound 298:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-[1-(6-fluoronaphthalen-2-yl)ethyl]piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 603; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.98 (dd, J=9.1 Hz, 5.8 Hz, 1H), 7.87 (d, J=8.6 Hz, 1H), 7.83 (s,1H), 7.66 (dd, J=10.4 Hz, 2.6 Hz, 1H), 7.56 (d, J=8.4 Hz, 1H), 7.44-7.36(m, 2H), 7.05 (s, 1H), 6.83 (dd, J=9.3 Hz, 2.5 Hz, 1H), 4.08 (s, 2H),3.62 (q, J=6.7 Hz, 1H), 3.48-3.35 (m, 5H), 3.34-3.24 (m, 1H), 2.47-2.26(m, 4H), 2.00-1.85 (m, 4H), 1.39 (d, J=6.7 Hz, 3H), 1.35-1.12 (m, 4H).

Compound 179:1-[4-[(5-fluoro-1-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)oxy]ethan-1-one

(ES, m/z): [M+H]⁺ 579.15; ¹H NMR (300 MHz, CDCl₃): δ 8.02 (d, J=9.0 Hz,1H), 7.41 (dd, J=3.9 Hz, 9.0 Hz, 1H), 7.27 (d, J=10.2 Hz, 1H), 7.07-7.14(m, 1H), 6.97 (s, 1H), 6.83 (d, J=5.4 Hz, 1H), 6.60 (dd, J=2.7 Hz, 9.0Hz, 1H), 4.37 (s, 2H), 4.17 (s, 2H), 4.01 (br s, 4H), 3.11-3.37(overlapping m, 6H), 2.00-2.15 (m, 4H), 1.15-1.44 (m, 4H).

Compound 304:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-[1-(5-fluorobenzofuran-2-yl)ethyl]piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 593; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.56 (dd, J=8.9 Hz, 4.2 Hz, 1H), 7.43-7.36 (m, 2H), 7.10-7.03 (m,2H), 6.82 (dd, J=9.2 Hz, 2.4 Hz, 1H), 6.75 (s, 1H), 4.08 (s, 2H), 3.98(q, J=7.0 Hz, 1H), 3.48-3.35 (m, 5H), 3.33-3.23 (m, 1H), 2.58-2.45 (m,2H), 2.43-2.32 (m, 2H), 2.00-1.83 (m, 4H), 1.42 (d, J=7.0 Hz, 3H),1.34-1.09 (m, 4H).

Compound 318:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(4,6-dichlorobenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 629; ¹H NMR (400 MHz, DMSO-d6): δ 8.06 (d, J=9.2 Hz,1H), 7.70 (d, J=2.0 Hz, 1H), 7.51 (d, J=2.0 Hz, 1H), 7.43 (d, J=7.7 Hz,1H), 7.06 (s, 1H), 6.91 (s, 1H), 6.84 (dd, J=9.2 Hz, 2.3 Hz, 1H), 4.12(s, 2H), 3.77 (s, 2H), 3.50-3.38 (m, 5H), 3.36-3.27 (m, 1H), 2.53-2.39(m, 4H), 2.03-1.87 (m, 4H), 1.39-1.14 (m, 4H).

Compound 319:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5,7-dichlorobenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 629; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.81 (s, 1H), 7.45 (d, J=1.6 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.06(s, 1H), 6.90 (s, 1H), 6.84 (dd, J=9.3 Hz, 2.5 Hz, 1H), 4.12 (s, 2H),3.75 (s, 2H), 3.50-3.38 (m, 5H), 3.36-3.27 (m, 1H), 2.52-2.40 (m, 4H),2.03-1.87 (m, 4H), 1.39-1.14 (m, 4H).

Compound 320:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(4,5-difluorobenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 597; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.48-7.40 (m, 2H), 7.38-7.29 (m, 1H), 7.06 (s, 1H), 7.01 (s, 1H),6.84 (dd, J=9.3 Hz, 2.5 Hz, 1H), 4.12 (s, 2H), 3.73 (s, 2H), 3.49-3.39(m, 5H), 3.35-3.27 (m, 1H), 2.52-2.41 (m, 4H), 2.03-1.88 (m, 4H),1.39-1.14 (m, 4H).

Compound 321:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5-chloro-7-bromobenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 673; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.72 (d, J=2.0 Hz, 1H), 7.60 (d, J=2.0 Hz, 1H), 7.43 (d, J=7.8 Hz,1H), 7.06 (s, 1H), 6.93 (s, 1H), 6.84 (dd, J=9.3 Hz, 2.3 Hz, 1H), 4.12(s, 2H), 3.77 (s, 2H), 3.50-3.38 (m, 5H), 3.36-3.26 (m, 1H), 2.53-2.40(m, 4H), 2.03-1.87 (m, 4H), 1.38-1.13 (m, 4H).

Compound 322:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(6-chlorobenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 595; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.73 (s, 1H), 7.61 (d, J=8.1 Hz, 1H), 7.43 (d, J=7.8 Hz, 1H), 7.26(d, J=8.5 Hz, 1H), 7.06 (s, 1H), 6.87-6.80 (m, 2H), 4.12 (s, 2H), 3.72(s, 2H) 3.48-3.38 (m, 5H), 3.36-3.27 (m, 1H), 2.52-2.39 (m, 4H),2.03-1.87 (m, 4H), 1.39-1.14 (m, 4H).

Compound 323:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5-methoxybenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 591; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.42 (d, J=9.0 Hz, 2H), 7.10 (d, J=2.6 Hz, 1H), 7.06 (s, 1H), 6.85(dd, J=8.9 Hz, 2.6 Hz, 2H), 6.71 (s, 1H), 4.12 (s, 2H), 3.75 (s, 3H),3.68 (s, 2H), 3.48-3.38 (m, 5H), 3.36-3.27 (m, 1H), 2.50-2.38 (m, 4H),2.03-1.88 (m, 4H), 1.38-1.14 (m, 4H).

Compound 325:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-(5,6-difluorobenzofuran-2-ylmethyl)piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 596; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.80 (dd, J=10.6 Hz, 6.6 Hz, 1H), 7.65 (dd, J=10.5 Hz, 8.2 Hz, 1H),7.43 (d, J=7.8 Hz, 1H), 7.06 (s, 1H), 6.86-6.80 (m, 2H), 4.12 (s, 2H),3.71 (s, 2H), 3.48-3.39 (m, 5H), 3.35-3.28 (m, 1H), 2.50-2.39 (m, 4H),2.03-1.88 (m, 4H), 1.39-1.15 (m, 4H).

Compound 326:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-[5-(trifluoromethoxy)benzofuran-2-ylmethyl]piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 645; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.67 (d, J=8.9 Hz, 1H), 7.63 (s, 1H), 7.42 (d, J=7.8 Hz, 1H), 7.25(dd, J=8.9 Hz, 2.5 Hz, 1H), 7.06 (s, 1H), 6.87 (s, 1H), 6.84 (dd, J=9.2Hz, 2.5 Hz, 1H), 4.12 (s, 2H), 3.74 (s, 2H), 3.49-3.39 (m, 5H),3.35-3.27 (m, 1H), 2.51-2.41 (m, 4H), 2.02-1.86 (m, 4H), 1.38-1.14 (m,4H).

Compound 338:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-[5-(trifluoromethyl)benzothiazole-2-carbonyl]piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 660; ¹H NMR (400 MHz, DMSO-d6): δ 8.52 (s, 1H), 8.48(d, J=8.5 Hz, 1H), 8.05 (d, J=9.2 Hz, 1H), 7.92 (dd, J=8.5 Hz, 1.4 Hz,1H), 7.45 (d, J=7.7 Hz, 1H), 7.07 (s, 1H), 6.85 (d, J=9.0 Hz, 1H),4.37-4.26 (m, 2H), 4.21 (s, 2H), 3.81-3.62 (m, 2H), 3.67-3.56 (m, 4H),3.52-3.34 (m, 2H), 2.09-1.90 (m, 4H), 1.45-1.14 (m, 4H).

Compound 299:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]-cyclohexyl)oxy]-1-[4-(5-bromobenzofuran-2-ylmethyl)-piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 641; ¹H NMR (400 MHz, DMSO-d6): δ 8.05 (d, J=9.2 Hz,1H), 7.44 (d, J=7.7 Hz, 1H), 7.37 (s, 1H), 7.22 (dd, J=8.5 Hz, 2.2 Hz,1H), 7.07 (s, 1H), 6.85 (dd, J=9.2 Hz, 2.3 Hz, 1H), 6.71 (d, J=8.4 Hz,1H), 5.04-4.90 (m, 1H) 4.13 (s, 2H), 3.52-3.22 (m, 6H) 2.99-2.91 (m,1H), 2.69-2.62 (m, 1H), 2.59-2.41 (m, 6H), 2.06-1.90 (m, 4H), 1.42-1.16(m, 4H).

Compound 380:2-[(4-[[4-nitro-3-(trifluoromethyl)phenyl]amino]cyclohexyl)-oxy]1-[4-[5-[4-(trifluoromethyl)phenyl]2,3-dihydrobenzofuran-2-ylmethyl]piperazin-1-yl]ethan-1-one

(CI, m/z): [M+H]⁺ 706; ¹H NMR (400 MHz, CD₂Cl₂): δ 8.01 (d, J=9.1 Hz,1H), 7.69-7.64 (m, 4H), 7.46 (s, 1H), 7.39 (d, J=8.2 Hz, 1H), 6.87 (d,J=2.5 Hz, 1H), 6.84 (d, J=8.3 Hz, 1H), 6.67 (dd, J=9.1 Hz, 2.6 Hz, 1H),4.63 (d, J=8.0 Hz, 1H), 4.17 (s, 2H), 3.66-3.29 (m, 6H), 3.08-3.02 (m,1H), 2.86-2.49 (m, 5H), 2.18-2.06 (m, 4H), 1.59-1.20 (m, 7H).

Compound 375:1-[4-(5,7-difluoro-benzooxazol-2-ylmethyl)-piperazin-1-yl]-2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-ethanone

(CI, m/z): [M+H]⁺ 597; ¹H NMR (400 MHz, DMSO-d₆): δ 8.05 (d, J=9.23 Hz,1H), 7.43 (d, J=7.86 Hz, 1H), 7.31 (dd, J=8.44, 2.44 Hz, 1H), 7.24 (ddd,J=11.08, 9.81, 2.39 Hz, 1H), 7.06 (s, 1H), 6.92 (d, J=2.98 Hz, 1H), 6.84(dd, J=9.27, 2.49 Hz, 1H), 4.12 (s, 2H), 3.76 (s, 2H), 3.44 (br. s.,5H), 2.44 (br. s., 4H), 1.95-2.02 (m, 2H), 1.92 (d, J=11.86 Hz, 2H),1.27-1.39 (m, 2H), 1.17-1.26 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ ppm−133.63 (dt, J=11.21, 2.97 Hz, 1F) −117.37-−117.11 (m, 1F) −59.15 (s,3F).

Example 36 Preparation of Compound 376

Step 1. Formation of 2-amino-4-trifluoromethylphenol

2-Nitro-4-trifluoromethylphenol (340 μL, 2.41 mmol) was dissolved inmethanol (50 mL) and processed through the H-Cube with a 10% Pd/CCatalyst cartridge at ambient temperature and pressure. The eluent wasconcentrated under reduced pressure to provide2-amino-4-trifluoromethylphenol as a light brown solid (438 mg, 100%).(CI, m/z): [M+H]⁺ 178, [M−H]⁻ 176; ¹H NMR (CDCl₃): δ 6.96 (d, J=2.0 Hz,1H), 6.89-6.94 (m, 1H), 6.74 (d, J=8.2 Hz, 1H), 4.10 (br s, 2H).

Step 2. Formation of 2-chloromethyl-5-trifluoromethyl-benzoxazole

2-Chloro-1,1,1-triethoxyethane (410 μL, 2.15 mmol) was added to asuspension of 2-amino-4-trifluoromethylphenol (370 mg, 1.79 mmol) inacetic acid (7 mL); during the addition the solution began to clear. Thesolution was heated at 120° C. (external temperature). After three hoursthe reaction mixture was cooled and the volatiles were removed underreduced pressure. Purification by silica gel chromatography, elutingwith a gradient of 0 to 10% ethyl acetate in heptanes, gave2-chloromethyl-5-trifluoromethyl-benzoxazole as a yellow oil (324 mg,77%). (CI, m/z): [M+H]⁺ 236; ¹H NMR (CDCl₃): δ 8.05 (s, 1H), 7.66-7.73(m, 2H), 4.79 (s, 2H); ¹⁹F NMR (376 MHz, CDCl₃): δ ppm −61.26 (s, 3F).

Step 3. Formation of2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzooxazol-2-ylmethyl)-piperazin-1-yl]-ethanone(#376)

A mixture of 2-chloromethyl-5-trifluoromethyl-benzoxazole (50 mg, 0.214mmol),2-[4-(4-Nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-piperazin-1-yl-ethanonehydrochloride (100 mg, 0.214 mmol), potassium carbonate (60 mg, 0.428mmol), and DMF (1 mL) was heated at 100° C. for two hours before thereaction mixture was cooled, diluted with EtOAc (60 mL), washed withwater (2×40 mL), washed with brine (1×40 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure to an orange residuethat was purified by silica gel chromatography, eluting with a gradientof 0 to 100% EtOAc in heptanes, to provide2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzooxazol-2-ylmethyl)-piperazin-1-yl]-ethanoneas a stiff, orange solid (69 mg, 51%). (CI, m/z): [M+H]⁺ 360; ¹H NMR(400 MHz, DMSO-d₆): δ 8.17 (s, 1H), 8.05 (d, J=9.23 Hz, 1H), 7.97 (d,J=8.54 Hz, 1H), 7.77 (dd, J=8.57, 1.44 Hz, 1H), 7.43 (d, J=7.71 Hz, 1H),7.06 (s, 1H), 6.84 (dd, J=9.30, 2.51 Hz, 1H), 3.99 (s, 2H) 4.12 (s, 2H),3.45 (br s, 5H), 2.52-2.64 (m, 4H), 1.95-2.04 (m, 2H), 1.92 (d, J=10.59Hz, 2H), 1.28-1.40 (m, 2H), 1.19-1.27 (m, 2H); ¹⁹F NMR (376 MHz,DMSO-d₆): δ ppm −59.45 (s, 3F) −59.17 (s, 3F).

Compound 233:1-[4-(6-chloro-2-naphthyl)piperazin-1-yl]-2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]ethanone

(CI, m/z): [M+H]⁺ 591; ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J=9.1 Hz,1H), 7.72 (d, J=1.9 Hz, 1H), 7.66 (dd, J=17.5, 9.0 Hz, 2H), 7.37 (dd,J=8.8, 2.1 Hz, 1H), 7.29 (dd, J=9.0, 2.4 Hz, 1H), 7.10 (d, J=2.3 Hz,1H), 6.85 (d, J=2.5 Hz, 1H), 6.64 (dd, J=9.1, 2.6 Hz, 1H), 4.45 (d,J=7.9 Hz, 1H), 4.27 (s, 2H), 3.72-3.88 (m, 4H), 3.35-3.55 (m, 2H), 3.30(d, J=4.3 Hz, 4H), 2.17 (d, J=10.2 Hz, 4H), 1.43-1.55 (m, 2H), 1.24-1.37(m, 2H).

1-[4-(6-chloro-4-methyl-2-quinolyl)piperazin-1-yl]-2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]ethanone(#270)

(CI, m/z): [M+H]⁺ 606; ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J=9.1 Hz,1H), 7.76 (d, J=2.3 Hz, 1H), 7.65 (d, J=8.9 Hz, 1H), 7.49 (dd, J=8.9,2.4 Hz, 1H), 6.82-6.90 (m, 2H), 6.64 (dd, J=9.1, 2.6 Hz, 1H), 4.46 (d,J=7.7 Hz, 1H), 3.65-3.89 (m, 8H), 4.27 (s, 2H), 3.32-3.54 (m, 2H), 2.59(d, J=0.6 Hz, 3H), 2.16 (d, J=10.1 Hz, 4H), 1.43-1.55 (m, 2H), 1.25-1.36(m, 2H).

1-[4-(6-fluoro-4-methyl-2-quinolyl)piperazin-1-yl]-2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]ethanone(#99)

(CI, m/z): [M+H]⁺ 590; ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J=9.1 Hz,1H), 7.71 (dd, J=9.1, 5.4 Hz, 1H), 7.42 (dd, J=9.8, 2.8 Hz, 1H),7.30-7.37 (m, 1H), 6.89 (s, 1H), 6.85 (d, J=2.6 Hz, 1H), 6.64 (dd,J=9.1, 2.6 Hz, 1H), 4.46 (d, J=7.6 Hz, 1H), 4.27 (s, 2H), 3.65-3.86 (m,8H), 3.33-3.55 (m, 2H), 2.59 (s, 3H), 2.10-2.25 (m, 4H), 1.44-1.55 (m,2H), 1.23-1.37 (m, 2H).

Compound 277:1-[4-(6-bromo-4-methyl-2-quinolyl)piperazin-1-yl]-2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]ethanone

(CI, m/z): [M+2]⁺652; ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J=9.1 Hz, 1H),7.92 (d, J=2.0 Hz, 1H), 7.54-7.66 (m, 2H), 6.83-6.88 (m, 2H), 6.64 (dd,J=9.1, 2.6 Hz, 1H), 4.45 (d, J=7.5 Hz, 1H), 4.27 (s, 2H), 3.67-3.89 (m,8H), 3.34-3.54 (m, 2H), 2.59 (s, 3H), 2.16 (d, J=10.3 Hz, 4H), 1.44-1.55(m, 2H), 1.23-1.37 (m, 2H).

Compound 278:4-[[4-[2-[4-(6-chloro-2-naphthyl)piperazin-1-yl]-2-oxo-ethoxy]cyclohexyl]amino]-2-methyl-benzonitrile

(CI, m/z): [M+H]⁺ 571; ¹H NMR (400 MHz, CD₃OD): δ 7.72 (d, J=1.9 Hz,1H), 7.66 (dd, J=17.6, 9.0 Hz, 2H), 7.55 (d, J=8.5 Hz, 1H), 7.37 (dd,J=8.7, 2.1 Hz, 1H), 7.28-7.31 (m, 1H), 7.10 (d, J=2.2 Hz, 1H), 6.81 (d,J=2.3 Hz, 1H), 6.66 (dd, J=8.6, 2.4 Hz, 1H), 4.24-4.35 (m, 3H),3.73-3.89 (m, 4H), 3.22-3.54 (m, 6H), 2.10-2.25 (m, 4H), 1.41-1.54 (m,2H), 1.21-1.35 (m, 2H).

Example 37 Preparation of Compound 235

Step 1. Formation of 2-(bromomethyl)-5-fluoro-1,3-benzothiazole

A mixture of 5-fluoro-2-methyl-1,3-benzothiazole (500 mg, 2.99 mmol),NBS (600 mg, 3.37 mmol) and AIBN (125 mg, 0.76 mmol) in carbontetrachloride (25 ml) was heated at reflux for 20 hours under nitrogenwith stirring. The solution was then concentrated to give a residuewhich was purified by silica gel column chromatography using 1% ethylacetate in petroleum ether to afford2-(bromomethyl)-5-fluoro-1,3-benzothiazole as a yellow solid (150 mg,20%). ¹H NMR (400 MHz, CDCl₃): δ 7.81 (dd, J=8.8, 5.2 Hz, 1H), 7.70 (dd,J=9.2, 2.4 Hz, 1H), 7.23-7.16 (m, 1H), 4.80 (s, 2H).

Step 2. Formation of 5-fluoro-2-(piperazin-1-ylmethyl)-1,3-benzothiazole

A mixture of 2-(bromomethyl)-5-fluoro-1,3-benzothiazole (150 mg, 0.61mmol), potassium carbonate (253 mg, 1.83 mmol) and piperazine (263 mg,3.05 mmol) in acetonitrile (30 ml) was heated at reflux for 4.5 hourswith stirring and was then concentrated under vacuum. The residue wasdissolved in dichloromethane (100 ml), washed with brine (3×50 mL),dried over anhydrous sodium sulfate, filtered and concentrated undervacuum to afford 5-fluoro-2-(piperazin-1-ylmethyl)-1,3-benzothiazole asa yellow crude solid (130 mg). (ES, m/z): [M+H]⁺ 252.1; ¹H NMR (400 MHz,CDCl₃): δ 7.81 (dd, J=8.8, 5.2 Hz, 1H), 7.70 (dd, J 9.6, 2.4 Hz, 1H),7.16-7.11 (m, 1H), 3.93 (s, 2H), 2.97-2.93 (m, 4H), 2.64-2.63 (m, 4H),1.98 (s, 1H).

Step 3. Formation of1-(4-((5-fluorobenzo[d]thiazol-2-yl)methyl)piperazin-1-yl)-2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethanone(#235)

A mixture of 5-fluoro-2-(piperazin-1-ylmethyl)-1,3-benzothiazole (130mg, 0.52 mmol), EDAC.HCl (149 mg, 0.78 mmol), HOBt (105 mg, 0.78 mmol)and triethylamine (157 mg, 1.55 mmol) in dichloromethane (30 ml) wasstirred for 1 hour at room temperature before the addition of2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)acetic acid(187 mg, 0.52 mmol). After stirring overnight at room temperature, thesolution was diluted with dichloromethane (100 ml) and washed with water(50 ml), dried over anhydrous sodium sulfate, filtered, and concentratedunder vacuum to give a residue, which was purified by HPLC to afford1-(4-((5-fluorobenzo[d]thiazol-2-yl)methyl)piperazin-1-yl)-2-(-4-(4-nitro-3-(trifluoromethyl)phenylamino)cyclohexyloxy)ethanoneas a yellow solid (162.0 mg, 53%).

(ES, m/z): [M+H]⁺ 596.00; ¹H NMR (300 MHz, CDCl₃): δ 8.01 (d, J=9.0 Hz,1H), 7.87 (dd, J=8.7, 4.8 Hz, 1H), 7.72 (dd, J=9.0, 2.4 Hz, 1H),7.29-7.23 (m, 1H), 6.84 (d, J=2.1 Hz, 1H), 6.62 (dd, J=9.0, 2.1 Hz, 1H),5.52 (br s, 1H), 4.47 (s, 2H), 4.20 (s, 2H), 3.93-3.90 (m, 4H),3.43-3.33 (m, 2H), 3.22-3.19 (m, 4H), 2.11-2.01 (m, 4H), 1.48-1.37 (m,2H), 1.32-1.21 (m, 2H).

Compound 294:4-[[4-[2-[4-[(5-fluoro-1,3-benzothiazol-2-yl)methyl]piperazin-1-yl]-2-oxo-ethoxy]cyclohexyl]amino]-2-(trifluoromethyl)benzonitrile

(CI, m/z): [M+H]⁺ 576; ¹H NMR (400 MHz, CD₃OD): δ 0.7.81 (dd, J=8.8, 5.1Hz, 1H), 7.66 (dd, J=9.4, 2.4 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.17 (td,J=8.8, 2.5 Hz, 1H), 6.81 (d, J 2.3 Hz, 1H), 6.66 (dd, J=8.6, 2.4 Hz,1H), 4.34 (d, J=7.4 Hz, 1H), 4.20 (s, 2H), 3.99 (s, 2H), 3.54-3.78 (m,4H), 3.28-3.50 (m, 2H), 2.67 (t, J=4.9 Hz, 4H), 2.13 (d, J=8.8 Hz, 4H),1.38-1.53 (m, 2H), 1.23-1.29 (m, 2H).

Compound 291:1-[4-[(5-chloro-1,3-benzothiazol-2-yl)methyl]piperazin-1-yl]-2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]ethanone

(CI, m/z): [M+H]⁺ 612; ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J=9.0 Hz,1H), 7.96 (d, J=1.9 Hz, 1H), 7.79 (d, J=8.5 Hz, 1H), 7.37 (dd, J=8.5,1.9 Hz, 1H), 6.85 (d, J=2.2 Hz, 1H), 6.64 (dd, J=9.0, 2.4 Hz, 1H), 4.48(d, J=7.6 Hz, 1H), 4.21 (s, 2H), 3.99 (s, 2H), 3.58-3.77 (m, 4H),3.33-3.49 (m, 2H), 2.67 (t, J=4.9 Hz, 4H), 2.14 (d, J=11.0 Hz, 4H),1.41-1.53 (m, 2H), 1.23-1.34 (m, 2H).

Compound 292:4-[[4-[2-[4-[(5-chloro-1,3-benzothiazol-2-yl)methyl]piperazin-1-yl]-2-oxo-ethoxy]cyclohexyl]amino]-2-(trifluoromethyl)benzonitrile

(CI, m/z): [M+H]⁺ 592; ¹H NMR (400 MHz, CD₃OD): δ 7.96 (d, J=1.9 Hz,1H), 7.79 (d, J=8.5 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H), 7.37 (dd, J=8.5,2.0 Hz, 1H), 6.81 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.6, 2.3 Hz, 1H), 4.30(d, J=7.7 Hz, 1H), 4.20 (s, 2H), 3.99 (s, 2H), 3.55-3.76 (m, 4H),3.28-3.49 (m, 2H), 2.58-2.74 (m, 4H), 2.13 (d, J=8.5 Hz, 4H), 1.38-1.53(m, 2H), 1.18-1.35 (m, 2H).

Compound 301:4-[[4-[2-oxo-2-[4-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]piperazin-1-yl]ethoxy]cyclohexyl]amino]-2-(trifluoromethyl)benzonitrile

(CI, m/z): [M+H]⁺ 626; ¹H NMR (400 MHz, CD₃OD): δ 8.24 (s, 1H), 8.00 (d,J=8.3 Hz, 1H), 7.63 (dd, J=8.4, 1.4 Hz, 1H), 7.55 (d, J=8.6 Hz, 1H),6.81 (d, J=2.4 Hz, 1H), 6.66 (dd, J=8.6, 2.4 Hz, 1H), 4.31 (d, J=7.3 Hz,1H), 4.21 (s, 2H), 4.02 (s, 2H), 3.59-3.77 (m, 4H), 3.30-3.48 (m, 2H),2.59-2.80 (m, 4H), 2.13 (d, J=9.9 Hz, 4H), 1.38-1.54 (m, 2H), 1.22-1.32(m, 2H).

Compound 302:2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]-1-[4-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]piperazin-1-yl]ethanone

(CI, m/z): [M+H]⁺ 646; ¹H NMR (400 MHz, CD₃OD): δ 8.24 (s, 1H), 8.01 (t,J=8.2 Hz, 2H), 7.63 (dd, J=8.5, 1.4 Hz, 1H), 6.85 (d, J=2.6 Hz, 1H),6.64 (dd, J=9.1, 2.6 Hz, 1H), 4.39-4.57 (m, 1H), 4.21 (s, 2H), 4.03 (s,2H), 3.59-3.80 (m, 4H), 3.33-3.50 (m, 2H), 2.68 (t, J=5.0 Hz, 4H), 2.14(d, J=11.0 Hz, 4H), 1.41-1.53 (m, 2H), 1.30 (m., 2H).

Compound 324:2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]-1-[4-[2-[5-(trifluoromethyl)benzofuran-2-yl]ethyl]piperazin-1-yl]ethanone

(CI, m/z): [M+H]⁺ 643; ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J=9.0 Hz,1H), 7.79 (s, 1H), 7.49 (d, J=1.1 Hz, 2H), 6.85 (d, J=2.5 Hz, 1H), 6.63(dd, J=9.1, 2.6 Hz, 1H), 6.53 (s, 1H), 4.51 (d, J=7.6 Hz, 1H), 4.20 (s,2H), 3.52-3.71 (m, 4H), 3.32-3.50 (m, 2H), 2.97-3.08 (m, 2H), 2.77-2.88(m, 2H), 2.54 (t, J=4.8 Hz, 4H), 2.15 (d, J=10.6 Hz, 4H), 1.40-1.55 (m,2H), 1.27-1.34 (m, 2H).

Compound 330:1-[4-[1-methyl-2-[5-(trifluoromethyl)benzofuran-2-yl]ethyl]piperazin-1-yl]-2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]ethanone

(CI, m/z): [M+H]⁺ 657; ¹H NMR (400 MHz, CD₃OD): δ 8.02 (d, J=9.1 Hz,1H), 7.79 (s, 1H), 7.49 (d, J=1.1 Hz, 2H), 6.85 (d, J=2.4 Hz, 1H), 6.64(dd, J=9.1, 2.6 Hz, 1H), 6.52 (s, 1H), 4.45 (d, J=7.5 Hz, 1H), 4.16-4.23(m, 2H), 3.63-3.51 (m, 4H), 3.46-3.38 (m, 2H), 3.21-3.16 (m, 1H),3.04-3.09 (m, 1H), 3.02-3.10 (m, 1H), 2.74 (dd, J=14.9, 8.2 Hz, 1H),2.55-2.65 (m, 3H), 2.13-2.16 (m, 4H), 1.43-1.51 (m, 2H), 1.24-1.34 (m,2H), 1.09 (d, J=6.6 Hz, 3H).

Example 38 Preparation of Compound 331

Steps 1-7

The formation of 2-piperazin-1-yl-6-(trifluoromethyl)quinolinehydrochloride is described in the synthesis of compound 89 with thedifference being the use of BOC-piperazine in lieu of piperazine.

Step 8. Formation of (trans)-4,-4(dibenzylamino)cyclohexanol

To a stirred solution of (trans)-4-aminocyclohexanol (5 g, 43 mmol, 1eq.) in 200 mL of acetonitrile was added potassium carbonate (21 g, 152mmol, 1 eq.) and benzylbromide (10.3 mL, 86.8 mmol, 2 eq.). The mixturewas stirred at room temperature for 16 hours and then filtered. Thefilter cake was washed with dichloromethane and the filtrate wasconcentrated under vacuum. The crude material was dissolved withdichloromethane, washed with water and then saturated ammonium chloride,dried over sodium sulfate, and concentrated. The crude material waspurified by silica gel column chromatography using ethylacetate/heptanes to elute. The product containing fractions werecombined and concentrated under vacuum to afford(trans)-4,-4(dibenzylamino)cyclohexanol as a white solid (8.9 g, 70%);(CI, m/z): [M+H]⁺ 296; ¹H NMR (400 MHz, CDCl₃): δ 7.34-7.39 (m, 4H),7.27-7.33 (m, 4H), 7.18-7.25 (m, 2H), 3.62 (s, 4H), 3.50-3.60 (m, 1H),2.48-2.59 (m, 1H), 2.01 (m, 2H), 1.86-1.95 (m, 2H), 1.58 (br s, 1H),1.38-1.50 (m, 2H), 1.14-1.26 (m, 2H).

Step 9. Formation of tert-butyl 2-[4-(dibenzylamino)cyclohexoxy]acetate

(Trans)-4,-4(dibenzylamino)cyclohexanol (8 g, 27 mmol, 1 eq.) wasdissolved in toluene (100 mL) and mixed with tetrabutylammonium hydrogensulfate (0.46 g, 1.35 mmol, 0.05 eq.) and tert-butyl bromoacetate (6 mL,40.61 mmol, 1.5 eq.). Sodium hydroxide solution (26 mL, 50% aq.) wasadded dropwise with vigorous stirring. The mixture was stirred for 3days at room temperature. After phase separation, the organic phase waswashed with water and saturated sodium chloride solution, dried oversodium sulfate, and then concentrated under vacuum. The resulting crudeproduct was purified by silica gel column chromatography using ethylacetate/heptanes to elute. The product containing fractions werecombined and concentrated under vacuum to afford tert-butyl2-[4-(dibenzylamino)cyclohexoxy]acetate (6.2 g, 56%); (CI, m/z): [M+H]⁺410; ¹H NMR (400 MHz, CDCl₃): δ 7.33-7.39 (m, 4H), 7.27-7.32 (m, 4H),7.18-7.24 (m, 2H), 3.97 (s, 2H), 3.61 (s, 4H), 3.21-3.31 (m, 1H),2.48-2.59 (m, 1H), 2.05-2.15 (m, 2H), 1.88-1.98 (m, 2H), 1.48 (s, 9H),1.33-1.45 (m, 2H), 1.15-1.27 (m, 2H).

Step 10. Formation of tert-butyl 2-(4-aminocyclohexoxy)acetate

Tert-butyl 2-[4-(dibenzylamino)cyclohexoxy]acetate (6 g, 15 mmol, 1 eq.)was dissolved in methanol (200 mL) and pumped through the H-Cube®hydrogenation instrument containing a 10% Pd(OH)₂ catalyst cartridge(CatCart) and using full hydrogen flow, ambient pressure, at 40° C. for3 hours. The solvent was removed under vacuum to provide tert-butyl2-(4-aminocyclohexoxy)acetate (3.3 g, 98%); (CI, m/z): [M+H]⁺ 230; ¹HNMR (400 MHz, CDCl₃): δ 3.99 (s, 2H), 3.31 (tt, J=10.7, 4.2 Hz, 1H),2.71 (tt, J=10.8, 3.9 Hz, 1H), 2.00-2.11 (m, 2H), 1.83-1.93 (m, 2H),1.46-1.51 (m, 9H), 1.29-1.44 (m, 4H), 1.06-1.19 (m, 2H).

Step 11. Formation of tert-butyl2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]acetate

A suspension of tert-butyl 2-(4-aminocyclohexoxy)acetate (0.5 g, 1.7mmol, 1 eq.), 1-bromo-4-(trifluoromethylsulfonyl)benzene (0.4 g, 1.7mmol, 1 eq.), cesium carbonate (1.4 g, 4.3 mmol, 2.5 eq.), and BINAP (54mg, 0.08 mmol, 0.05 eq.), in toluene (15 mL), was bubbled with nitrogenfor 10 minutes before the addition of Pd(OAc)₂ (19 mg, 0.08 mmol, 0.05eq.) to the reaction mixture. Nitrogen gas was bubbled through thereaction mixture for another 10 minutes and the contents were heated at100° C. under nitrogen atmosphere for 3 hours. The contents were cooledto room temperature, diluted with ethyl acetate, filtered throughCelite®, and concentrated. The crude material was purified by silica gelcolumn chromatography using ethyl acetate/heptanes to elute. The productcontaining fractions were combined and concentrated to obtain tert-butyl2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]acetate (0.73 g,77%); (CI, m/z): [M+H]⁺ 438; ¹H NMR (400 MHz, CDCl₃): δ 7.74 (d, J=8.9Hz, 2H), 6.56-6.70 (m, 2H), 4.44 (d, J=7.4 Hz, 1H), 4.02 (s, 2H),3.32-3.49 (m, 2H), 2.07-2.25 (m, 4H), 1.44-1.55 (m, 11H), 1.21-1.35 (m,2H).

Step 12. Formation of trufluoro acetic acid salt of2-[4-[4-(trifluoromethylsulfonyl) anilino]cyclohexoxy]acetic acid

To a solution of tert-butyl 2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]acetate (0.7 g, 1.6 mmol, 1 eq.) in trifluroaceticacid (3 mL) was stirred at room temperature for 2 hours. The mixture wasconcentrated under vacuum to remove excess trifluoroacetic acid. Thecrude material was dried under high vacuum overnight to obtain2-[4-[4-(trifluoromethylsulfonyl) anilino]cyclohexoxy]acetic acid aslight brown syrup. (0.79 g, 100%); (CI, m/z): [M+H]⁺ 382; ¹H NMR (400MHz, CD₃OD): δ 7.65 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.2 Hz, 2H), 4.13 (s,2H), 3.37-3.51 (m, 2H), 2.03-2.20 (m, 4H), 1.26-1.54 (m, 4H).

Step 13. Formation of1-[4-[6-(trifluoromethyl)-2-quinolyl]piperazin-1-yl]-2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]ethanone(#331)

To a solution of2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]acetic acid (75 mg,0.19 mmol, 1 eq.) in DMF (1 ml) was added EDAC.HCl (56 mg, 0.29 mmol,1.5 eq.), HOBt (39 mg, 0.29 mmol, 1.5 eq.), 4-methylmorpholine (0.21 mL,1.96 mmol, 10 eq.), and 2-piperazin-1-yl-6-(trifluoromethyl)quinolinehydrochloride (62 mg, 0.19 mmol, 1 eq.). The resulting solution wasstirred overnight at room temperature and concentrated to remove DMFunder vacuum. The resulting crude material was diluted with water,extracted with ethyl acetate, dried over sodium sulfate and concentratedto get crude. The crude material was purified by silica gel columnchromatography using ethyl acetate/dichloromethane to elute. The productcontaining fractions were combined and concentrated under vacuum toafford 89 mg of1-[4-[6-(trifluoromethyl)-2-quinolyl]piperazin-1-yl]-2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]ethanone as white solid (70%); (CI, m/z): [M+H]⁺645; ¹H NMR (400 MHz, CD₃OD): δ 7.99 (d, J=9.2 Hz, 1H), 7.92 (s, 1H),7.69-7.81 (m, 4H), 7.06 (d, J=9.2 Hz, 1H), 6.63 (d, J=9.0 Hz, 2H), 4.44(d, J=7.6 Hz, 1H), 4.27 (s, 2H), 3.86-3.97 (m, 2H), 3.80 (m, 4H),3.69-3.76 (m, 2H), 3.35-3.55 (m, 2H), 2.12-2.25 (m, 4H), 1.45-1.55 (m,2H), 1.26-1.35 (m, 2H).

Compound 344:1-[4-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]piperazin-1-yl]-2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]ethanone

(CI, m/z): [M+H]⁺ 665; ¹H NMR (400 MHz, CD₃OD): δ 8.24 (s, 1H), 8.00 (d,J=8.3 Hz, 1H), 7.74 (d, J=8.9 Hz, 2H), 7.63 (dd, J=8.4, 1.4 Hz, 1H),6.60-6.68 (m, 2H), 4.43 (d, J 7.3 Hz, 1H), 4.21 (s, 2H), 4.02 (s, 2H),3.60-3.75 (m, 4H), 3.35-3.48 (m, 2H), 2.65-2.72 (m, 4H), 2.11-2.20 (m,4H), 1.41-1.52 (m, 2H), 1.27-1.33 (m, 2H).

Compound 378:1-[4-[[5-(trifluoromethyl)-2,3-dihydrobenzofuran-2-yl]methyl]piperazin-1-yl]-2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]ethanone

(CI, m/z): [M+H]⁺ 650; ¹H NMR (400 MHz, CD₃OD): δ 7.71 (d, J=8.8 Hz,2H), 7.33-7.44 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 6.55-6.65 (m, 2H),4.95-5.11 (m, 1H), 4.44 (d, J=7.6 Hz, 1H), 4.18 (s, 2H), 3.52-3.69 (m,4H), 3.24-3.45 (m, 3H), 3.00 (dd, J=15.8, 7.7 Hz, 1H), 2.77 (dd, J=13.6,7.5 Hz, 1H), 2.51-2.67 (m, 5H), 2.12 (m, 4H), 1.38-1.50 (m, 2H),1.23-1.31 (m, 2H).

Compound 379:1-[4-[(5-fluoro-2,3-dihydrobenzofuran-2-yl)methyl]piperazin-1-yl]-2-[4-[4-(trifluoromethylsulfonyl)anilino]cyclohexoxy]ethanone

(CI, m/z): [M+H]⁺ 600; ¹H NMR (400 MHz, CD₃OD): δ 7.74 (d, J=8.9 Hz,2H), 6.88 (dd, J=7.9, 2.6 Hz, 1H), 6.76-6.83 (m, 1H), 6.69 (dd, J=8.6,4.2 Hz, 1H), 6.61-6.66 (m, 2H), 4.92-5.04 (m, 1H), 4.43 (d, J=7.3 Hz,1H), 4.20 (s, 2H), 3.54-3.71 (m, 4H), 3.34-3.49 (m, 2H), 3.27 (dd,J=15.8, 9.1 Hz, 1H), 2.97 (dd, J=15.6, 8.1 Hz, 1H), 2.79 (dd, J=13.5,7.6 Hz, 1H), 2.53-2.68 (m, 5H), 2.09-2.21 (m, 4H), 1.41-1.52 (m, 2H),1.27-1.34 (m, 2H).

Compound 335:4-[[4-[2-oxo-2-[4-(3-quinolyl)piperazin-1-yl]ethoxy]cyclohexyl]amino]-2-(trifluoromethyl)benzonitrile

(CI, m/z): [M+H]⁺ 538; ¹H NMR (400 MHz, CD₃OD): δ 8.81 (d, J=2.8 Hz,1H), 8.02 (d, J=8.3 Hz, 1H), 7.70 (dd, J=8.1, 1.2 Hz, 1H), 7.46-7.61 (m,3H), 7.38 (d, J=2.7 Hz, 1H), 6.81 (d, J=2.3 Hz, 1H), 6.66 (dd, J=8.6,2.4 Hz, 1H), 4.32 (d, J=7.6 Hz, 1H), 4.27 (s, 2H), 3.77-3.92 (m, 4H),3.27-3.49 (m, 6H), 2.08-2.22 (m, 4H), 1.43-1.55 (m, 2H), 1.26-1.34 (m,2H).

Compound 336:2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]-1-[4-(3-quinolyl)piperazin-1-yl]ethanone

(CI, m/z): [M+H]⁺ 558; ¹H NMR (400 MHz, CD₃OD): δ 8.81 (d, J=2.8 Hz,1H), 8.02 (d, J=9.0 Hz, 2H), 7.71 (dd, J=8.1, 1.1 Hz, 1H), 7.48-7.60 (m,2H), 7.38 (d, J=2.8 Hz, 1H), 6.85 (d, J=2.5 Hz, 1H), 6.64 (dd, J=9.1,2.6 Hz, 1H), 4.46 (d, J=7.6 Hz, 1H), 4.27 (s, 2H), 3.77-3.92 (m, 4H),3.37-3.53 (m, 2H), 3.32 (m, 4H), 2.10-2.24 (m, 4H), 1.46-1.56 (m, 2H),1.27-1.35 (m, 2H).

Compound 377:1-[4-[(5-fluoro-2-methyl-3H-benzofuran-2-yl)methyl]piperazin-1-yl]-2-[4-[4-nitro-3-(trifluoromethyl)anilino]cyclohexoxy]ethanone

(CI, m/z): [M+H]⁺ 595; ¹H NMR (400 MHz, CD₃OD): δ 8.01 (d, J=9.1 Hz,1H), 6.82-6.90 (m, 2H), 6.78 (td, J=8.9, 2.8 Hz, 1H), 6.55-6.66 (m, 2H),4.59 (d, J=7.7 Hz, 1H), 4.17 (s, 2H), 3.32-3.61 (m, 6H), 3.26 (d, J=15.7Hz, 1H), 2.88 (d, J=15.7 Hz, 1H), 2.49-2.68 (m, 6H), 2.13 (d, J=10.6 Hz,4H), 1.38-1.53 (m, 5H), 1.25-1.33 (m, 2H).

Example 39 Preparation of Compound 400

2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethyl-benzooxazol-2-yl)-piperazin-1-yl]-ethanone

(CI, m/z): [M+H]⁺ 616; ¹H NMR (DMSO-d₆): δ 8.05 (d, J=9.2 Hz, 1H), 7.63(dd, J=5.1, 3.3 Hz, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.40 (dd, J=8.7, 1.5Hz, 1H), 7.06 (s, 1H), 6.85 (dd, J=9.3, 2.4 Hz, 1H), 4.22 (s, 2H),3.57-3.74 (m, 8H), 3.43-3.51 (m, 1H), 3.34-3.43 (m, 1H), 2.04 (d, J=12.9Hz, 2H), 1.96 (d, J=12.3 Hz, 2H), 1.31-1.44 (m, 2H), 1.19-1.30 (m, 2H);¹⁹F NMR (376 MHz, DMSO-d₆): δ −59.45 (s, 3H), −59.15 (s, 3H).

2-[4-(4-nitro-3-trifluoromethyl-phenylamino)-cyclohexyloxy]-1-[4-(5-trifluoromethoxy-benzooxazol-2-yl)-piperazin-1-yl]ethanone

(CI, m/z): [M+H]⁺ 632; ¹H NMR (DMSO-d₆): δ 8.05 (d, J=9.2 Hz, 1H), 7.51(d, J=8.6 Hz, 1H), 7.45 (d, J=7.8 Hz, 1H), 7.31 (d, J=1.4 Hz, 1H), 7.06(s, 1H), 7.01 (dd, J=8.6, 1.5 Hz, 1H), 6.85 (dd, J=9.3, 2.5 Hz, 1H),4.21 (s, 2H), 3.56-3.72 (m, 8H), 3.43-3.52 (m, 1H), 3.36-3.42 (m, 1H),2.04 (d, J=9.5 Hz, 2H), 1.96 (d, J=12.7 Hz, 2H), 1.32-1.44 (m, 2H),1.19-1.31 (m, 2H); ¹⁹F NMR (376 MHz, DMSO-d₆): δ −59.15 (s, 3H), −57.15(s, 3H).

4-nitro-N-[4-[2-oxo-2-[4-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]piperazin-1-yl]ethoxy]cyclohexyl]benzenesulfonamide(#403)

(CI, m/z): [M+H]⁺ 642; ¹H NMR (400 MHz, CDCl₃): δ 8.33-8.42 (m, 2H),8.23 (s, 1H), 8.04-8.10 (m, 2H), 7.99 (d, J=8.4 Hz, 1H), 7.63 (dd,J=8.4, 1.4 Hz, 1H), 4.64 (d, J=7.6 Hz, 1H), 4.14 (s, 2H), 4.00 (s, 2H),3.63-3.73 (m, 2H), 3.54-3.62 (m, 2H), 3.17-3.37 (m, 2H), 2.50-2.76 (m,4H), 1.86-2.03 (m, 4H), 1.18-1.37 (m, 4H).

Compound 402:4-nitro-N-[4-[2-oxo-2-[4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]piperazin-1-yl]ethoxy]cyclohexyl]benzenesulfonamide

(CI, m/z): [M+H]⁺ 628; ¹H NMR (400 MHz, DMSO-d₆): δ 8.36-8.47 (m, 2H),7.98-8.11 (m, 4H), 7.72 (d, J=1.2 Hz, 1H), 7.39 (dd, J=8.3, 1.2 Hz, 1H),4.13 (s, 2H), 3.50-3.69 (m, 8H), 3.18-3.27 (m, 1H), 2.99-3.12 (m, 1H),1.83-1.96 (m, 2H), 1.57-1.69 (m, 2H), 1.10-1.27 (m, 4H).

Compound 405:4-nitro-N-[4-[2-oxo-2-[4-[[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]methyl]piperazin-1-yl]ethoxy]cyclohexyl]-3-(trifluoromethyl)benzenesulfonamide

(CI, m/z): [M+H]⁺ 710; ¹H NMR (400 MHz, CDCl₃): δ 8.32 (d, J=1.71 Hz,1H), 8.21-8.25 (m, 2H), 8.00 (dd, J=8.4, 2.7 Hz, 2H), 7.63 (dd, J=8.4,1.3 Hz, 1H), 4.77 (d, J=7.7 Hz, 1H), 4.15 (s, 2H), 4.01 (s, 2H),3.55-3.73 (m, 4H), 3.21-3.38 (m, 2H), 2.66 (br s, 4H), 1.87-2.07 (m,4H), 1.21-1.41 (m, 4H).

Compound 404:4-nitro-N-[4-[2-oxo-2-[4-[5-(trifluoromethyl)-1,3-benzothiazol-2-yl]piperazin-1-yl]ethoxy]cyclohexyl]-3-(trifluoromethyl)benzenesulfonamide

(CI, m/z): [M+H]⁺ 696; ¹H NMR (400 MHz, DMSO-d₆): δ 8.31-8.42 (m, 3H),8.19 (d, J=7.1 Hz, 1H), 8.03 (d, J=8.2 Hz, 1H), 7.73 (br s, 1H), 7.39(dd, J=8.2, 1.2 Hz, 1H), 4.14 (s, 2H), 3.52-3.68 (m, 8H), 3.19-3.29 (m,1H), 3.06-3.17 (m, 1H), 1.84-1.96 (m, 2H), 1.58-1.71 (m, 2H), 1.17-1.26(m, 4H).

Biological Activity Examples Method A Screening Method to Test Activityof Compounds Against Haemonchus contortus

Twenty L1 Haemonchus contortus larvae were added to wells of amicrotitre plate containing a nutrient medium and the test compound inDMSO. An analysis was conducted at 4 days to determine the extent ofdevelopment of the larvae. Larvae exposed to DMSO alone served ascontrols. Compounds numbers 13, 14, 16, 17, 18, 24, 68, 75, 76, 77, 78,79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 96, 97, 98,99, 100, 103, 131, 172, 173, 174, 178, 179, 180, 181, 182, 183, 184,185, 186, 187, 188, 189, 191, 194, 216, 217, 218, 219, 220, 222, 223,225, 226, 227, 232, 233, 234, 235, 236, 237, 238, 239, 240, 241, 245,246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 260,260-10, 261, 262, 262-10, 263, 264, 265, 266, 267, 268, 269, 270, 271,272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 285, 287,288, 289, 290, 291, 292, 293, 294, 297, 298, 299, 300, 301, 302, 304,305, 306, 307, 308, 309, 310, 311, 312, 313, 315, 316, 318, 319, 320,321, 322, 323, 324, 325, 326, 327, 328, 329, 330, 331, 332, 333, 334,335, 336, 338, 342, 343, 344, 357, 358, 364, 365, 370, 371, 372, 373,374, 375, 377, 381, 399, 400, and 401 gave at least 90% motilityinhibition at a test concentration of less than or equal to 5 ppm whenassessed at the 4 day time point.

Method B Screening Method to Test Activity of Compounds Against anAnthelmintic-Resistant Isolate of Haemonchus contortus

The conditions described in method A were used against an isolate of H.contortus found to be functionally resistant against the benzimidazoleclass of anthelmintics (e.g. 127-fold resistance to thiabendazole).Analogs 14, 16, 17, 24, 76, 77, 78, 79, 83, 84, 88, 89, 90, 97, 99, 178,179, 180, 183, 185, 187, 188, 191, 217, 219, 232, 233, 234, 235, 236,237, 245, 246, 247, 248, 260, 260-10, 261, 262, 262-10, 265, 266, 269,270, 271, 272, 273, 278, 279, 281, 282, 283, 287, 289, 290, 291, 293,297, 298, 299, 300, 301, 302, 304, 307, 310, 311, 320, 325, 326, 327,328, 329, 330, 331, 332, 335, 342, 343, 344, 357, 358, 364, 365, & 370were evaluated and found to be of similar efficacy to that observedagainst the wild-type strain of H. contortus.

Method C Screening Method to Test Activity of Compounds Against Cooperiaoncophora In Vitro

Twenty L1 Cooperia oncophora larvae were added to the wells of amicrotitre plate containing a nutrient medium and the test compound inDMSO. An analysis was conducted at 4 days to determine the extent ofdevelopment of the larvae. Larvae exposed to DMSO alone served ascontrols. Compounds 76, 77, 78, 89, 90, 97, 99, 178, 180, 183, 234, 235,237, 245, 246, 260, 261, 262, 266, 269, 270, 271, 272, 273, 278, 281,282, 283, 289, 290, 291, 297, 298, 299, 300, 301, 302, 303, 304, 307,310, 320, 325, 326, 328, 331, 342, 343, 344 gave at least 90% inhibitionof motility at a test concentration of less than 5 ppm when assessed atthe 4 day time point.

Method D Method to Test Activity of Compounds Against Haemonchuscontortus In Vivo in Mongolian Jirds (Meriones unguiculatus)

Mongolian jirds, at least five weeks old, that have beenimmunosuppressed were artificially infected with ensheathed Haemonchuscontortus third instar larvae. Six days after infection, the jirds weretreated by oral gavage with the test compounds, dissolved in a mixtureof DMSO/corn oil, at doses of 30 mg/kg. Jirds treated only with theplacebo (DMSO/corn oil carrier) served as controls. On day 9 (3 daysafter treatment) the jirds were euthanized and necropsied for recoveryof parasites from the stomach. Efficacy was calculated as the average %reduction in the number of worms in each test group compared with theaverage number of worms from the control group. Compounds numbers 235,272, 278, 325, and 327 provided a 70-90% reduction in nematodeinfestation in Mongolian jirds treated by oral gavage with the testarticle at a dose of 30 mg/kg. Compounds numbers 77, 78, 89, 180, 245,261, 273, 283, 302, and 342 provided a >90% reduction in nematodeinfestation in Mongolian jirds treated by oral gavage with the testarticle at a dose of 30 mg/kg.

Method E

Method to test activity of compounds against Trichostrongyluscolubriformis in vivo in Mongolian jirds (Meriones unguiculatus).Mongolian jirds, at least five weeks old, that have beenimmunosuppressed were artificially infected with ensheathedTrichostrongylus colubriformis third instar larvae. Six days afterinfection, the jirds were treated by oral gavage with the testcompounds, dissolved in a mixture of DMSO/corn oil, at doses of 30mg/kg. Jirds treated only with the placebo (DMSO/corn oil carrier)served as controls. On day 9 (3 days after treatment) the jirds wereeuthanized and necropsied for recovery of parasites from the stomach.Efficacy was calculated as the average % reduction in the number ofworms in each test group compared with the average number of worms fromthe control group. In this method, a reduction in nematode infestationis achieved with compounds of formula (I), especially from table 1.Compounds numbers 77 & 89 provided a 60-80% reduction in nematodeinfestation in Mongolian jirds treated by oral gavage with the testarticle at a dose of 30 mg/kg. In particular, compounds numbers 78, 302,and 342 provided a >80% reduction in nematode infestation in Mongolianjirds treated by oral gavage with the test article at a dose of 30mg/kg.

Method F Screening Method to Test Activity of Compounds AgainstMicrofilaria of Dirofilaria immitis

Microfilaria of Dirofilaria immitis were added to the wells of amicrotitre plate containing buffer and the test compounds in DMSO. Anassessment was conducted at 24 hours to determine survival of themicrofilaria. Microfilaria exposed to DMSO alone served as controls.Compounds 15, 76, 77, 78, 79, 83, 84, 87, 88, 89, 93, 94, 95, 96, 98,100, 103, 104, 114, 160, 161, 182, 188, 189, 230, 231, 232, 257, 269,277, 279, 284, 287, 294, and 304 were found to have EC₅₀ values of lessthan 5 ppm, compounds 13, 14, 17, 18, 19, 20, 24, 81, 92, 97, 99, 101,102, 172, 178, 179, 180, 181, 183, 184, 186, 187, 192, 193, 194, 195,210, 216, 217, 218, 219, 220, 221, 225, 226, 227, 229, 233, 235, 236,242, 245, 246, 247, 249, 250, 251, 252, 254, 255, 256, 258, 260, 262,263, 265, 270, 271, 272, 273, 274, 275, 278, 290, 292, 297, 298, and260-10 returned EC₅₀ values of less than 1 ppm, and compounds 90, 185,222, 223, 234, 237, 248, 253, 261, 266, 299, 300, 301, 302, 305, 306,307, 308, 309, 310, and 262-10 returned EC₅₀ values of less than 0.1ppm.

Method D Permeability of Compounds

Permeability of a compound across the epithelium cells along thegastrointestinal tract is an important limiting factor for the oralabsorption and systemic availability of the compound. An in vitro modelutilizing Caco-2/TC7 cells is employed to assess the permeabilitycharacteristics of new chemical entities (NCEs). For orally administeredcompounds, absorption depends on the intrinsic permeability across theintestinal epithelium and whether the active agent is a substrate orinhibitor of uptake or efflux transporters. The permeability studieswere performed under standard conditions in the apical to basolateral(A→B) direction with a pH gradient and a BSA gradient (standard apicalmedium (0.5% BSA at pH 6.5)/standard basal medium (5% BSA at pH 7.4));conditions that most closely reflect the conditions in the in vivosituation. Samples were deproteinized by the addition of 400 μlacetonitrile to 200 μl sample, followed by a 20-minute centrifugation at1730 g. Compound solubilisation: compound solutions at finalconcentrations of 20 μM were prepared following dilutions of stocksolutions (starting from 10 mM in DMSO) in HBSS. Final concentration ofDMSO was adjusted to 1%. Analytical conditions: Supernatants recoveredfollowing centrifugation were analysed by LC/MS/MS using a reverse phasecolumn and the mobile phases delivered at 0.3 ml/minute in a gradient:water (A) and acetonitrile (B) (each with 0.1% formic acid).

The permeability of standard compounds in the CACO-2/TC7 in vitro modelfor permeability is shown in table 9. Every experiment (n) representsthe mean of 3 filters per experiment.

TABLE 9 Permeability as measured in the CACO-2/TC7 model. Permeability(A-B) Compound # [×10⁻⁷ cm/sec] 335 150 235 138 235 138  80 121 285 120334 119 323 119 287 110 301 99  24 97 274 92 325 90 304 90 306 90 292 83294 82 261 82 333 81 254 80 322 79 336 79 221 75 328 72  82 71 327 69320 68 332 65 291 62 297 57 329 56 187 55 256 54  84 53 222 50 178 49234 40 CC-1 25

Relative to the prior art compound CC-1 (described in WO2009/077527),compounds 234, 178, & 222 were 50-100% more permeable, compounds 84,256, 187, 329, 297, 291, 332, 320, 327, 82, 328, & 221 were 100-200%more permeable, compounds 336, 322, 254, 333, 261, 294, 292, 306, 304,325, 274, 24, & 301 were 200-300% more permeable, and compounds 287,323, 334, 285, 80, 235, & 335 were over 300% more permeable in theintestinal cell model.

Having thus described in detail preferred embodiments of the presentinvention, it is to be understood that the invention defined by theabove paragraphs is not to be limited to particular details set forth inthe above description as many apparent variations thereof are possiblewithout departing from the spirit or scope of the present invention.

What is claimed is:
 1. An anthelmintic compound of formula (I):

wherein: Y and Z are independently a bicyclic carbocyclic or a bicyclicheterocyclic group optionally substituted by one or more of halogen,nitro, cyano, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino,aminoalkyl, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio,haloalkylthio, alkylsulfinyl, haloalkylsulfinyl, alkylsulfonyl,haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio,arylsulfinyl, aryl sulfonyl, arylalkylsulfinyl, arylalkylsulfonyl,heteroaryl, heteroaryloxy, heteroarylalkoxy, heteroarylthio,heteroarylsulfinyl, heteroarylsulfonyl, heteroarylalkylthio,heteroarylalkylsulfinyl or heteroarylalkylsulfonyl; or one of Y or Z isa bicyclic carbocyclic or a bicyclic heterocyclic group optionallysubstituted by one or more of halogen, nitro, cyano, hydroxy,hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl,haloalkyl, alkoxy, haloalkoxy, alkylthio, halothio, haloalkylthio,alkylsulfinyl, haloalkylsulfinyl, alkyl sulfonyl, haloalkylsulfonyl,aryl, aryloxy, arylalkoxy, arylthio, arylalkylthio, arylsulfinyl, arylsulfonyl, arylalkylsulfinyl, arylalkylsulfonyl, heteroaryl,heteroaryloxy, heteroarylalkoxy, heteroarylthio, heteroarylsulfinyl,heteroarylsulfonyl, heteroarylalkylthio, heteroarylalkylsulfinyl orheteroarylalkylsulfonyl, and the other of Y or Z is alkyl, alkenyl,alkynyl, cycloalkyl, phenyl, heterocyclyl or heteroaryl; wherein thealkyl, alkenyl, alkynyl, cycloalkyl, phenyl, heterocyclyl and heteroarylgroups are optionally substituted with one or more substituentsindependently selected from selected from the group consisting ofhalogen, nitro, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkylthio,halothio, haloalkylthio, alkylsulfinyl, haloalkylsulfinyl,alkylsulfonyl, haloalkylsulfonyl, aryl, aryloxy, arylalkoxy, arylthio,arylalkylthio, arylsulfinyl, aryl sulfonyl, arylalkylsulfinyl,arylalkylsulfonyl, heteroaryl, heteroaryloxy, heteroarylalkoxy,heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl,heteroarylalkylthio, heteroarylalkylsulfinyl andheteroarylalkylsulfonyl; X₁ is a bond, —O—, —C(O)—, —C(S)—, —NR¹, —S,—S(O), —S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH—, —(CH₂)_(n)— wheren is 1 to 3, —C(O)—CH₂—, —CH₂—C(O)—, —O—CH₂—, —CH₂—O—, —NHCH₂—,—CH₂—NH—, —S—CH₂—, —CH₂—S—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, or—CH₂—S(O)₂—, wherein each NH, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH—,—(CH₂)_(n), —C(O)CH₂—, —CH₂—C(O)—, —O—CH₂—, —CH₂—O, —NH—CH₂, —CH₂—NH—,—S—CH₂—, —CH₂—S—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂— and —CH₂—S(O)₂—are optionally substituted with oxo (═O) or one or more halogen, cyano,hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl,alkyl, haloalkyl, cycloalkyl or aryl groups; X₂ is a linker selectedfrom a C₁-C₈-alkylene group, a C₂-C₈-alkenylene group, aC₂-C₈-alkynylene group, a 3-8 membered monocyclic carbocyclylene, a 3-8membered heterocyclylene group, a 7-11bicyclic carbocyclylene and a 7-11membered heterocyclylene group wherein the 3-8 membered heterocyclylenegroup and 7-11 membered heterocyclylene group may contain one to fournitrogen, oxygen or sulfur atoms, and wherein one to three of the carbonatoms in the C₁-C₈-alkylene group, the C₂-C₈-alkenylene group and theC₂-C₈-alkynylene group may be replaced by a nitrogen, an oxygen orsulfur atom; and wherein the C₁-C₈-alkylene group, the C₂-C₈-alkenylenegroup, the C₂-C₈-alkynylene group, the 3-8 membered carbocyclylene andthe 3-8 membered heterocyclylene group are optionally substituted withone or more substituents independently selected from halogen, alkyl,haloalkyl, alkoxy, haloalkoxy, hydroxy, hydroxyalkyl, amino, alkylamino,dialkylamino, aminoalkyl, and oxo (═O); X₃ is a diradical group selectedfrom the group consisting of a bond, —(CH₂)_(n)— where n is 1 to 3, —O—,—C(S)—, —C(O)—, —S(O)—, —S(O)₂—, and an oxetane group, wherein X₂ and X₄may be bonded to any carbon atom of the oxetane group; and wherein each—CH₂— in the —(CH₂)_(n)— group is optionally substituted with one or twosubstituents independently selected from the group consisting ofhalogen, hydroxy, hydroxyalkyl, amino, alkylamino, dialkylamino,aminoalkyl, alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl,haloalkynyl, carbocyclyl and halocarbocyclyl; X₄ is a bond, —(CH₂)_(n)—where n is 1 to 3, carbocyclylene or heterocyclylene, wherein the —CH₂—,the carbocyclylene and the heterocyclylene groups are optionallysubstituted with one or more substituents independently selected fromthe group consisting of halogen, hydroxy, hydroxyalkyl, amino,alkylamino, dialkylamino, aminoalkyl, alkyl, haloalkyl, alkenyl,haloalkenyl, alkynyl, haloalkynyl, carbocyclyl and halocarbocyclyl; X₅is a bond, —(CH₂)_(n) where n is 1 to 3, carbocyclylene orheterocyclylene, wherein each —CH₂— in the —(CH₂)_(n) group, thecarbocyclylene and the heterocyclylene groups are optionally substitutedwith one or more substituents independently selected from the groupconsisting of halogen, hydroxy, hydroxyalkyl, amino, alkylamino,dialkylamino, aminoalkyl, alkyl, haloalkyl, alkenyl, haloalkenyl,alkynyl, haloalkynyl, carbocyclyl and halocarbocyclyl; X₆ is a bond,—(CH₂)_(n)— where n is 1 to 3, —O—, —C(O)—, —C(S)—, —S—, —S(O)—,—S(O)₂—, —NH—, —C(O)—NH—, —C(S)—NH—, —NH—C(O)—, —NH—C(S)—, wherein each—CH₂— in the —(CH₂)_(n)— group, —NH—, —C(O)—NH—, —C(S)—NH—, —NH—C(O)—,—NH—C(S)— are optionally substituted with one or more substituentsindependently selected from the group consisting of halogen, hydroxy,hydroxyalkyl, amino, alkylamino, dialkylamino, aminoalkyl, alkyl,haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, carbocyclyl,halocarbocyclyl, carbocyclylalkyl and halocarbocyclylalkyl; X₇ is abond, —(CH₂)_(n)— where n is 1 to 3, alkenylene, alkynylene,carbocyclylene or heterocyclylene, wherein each CH₂ in —(CH₂)_(n)—,alkenylene, alkynylene, carbocyclylene and heterocyclylene is optionallysubstituted with one or more halogen, hydroxy, hydroxyalkyl, alkoxy,haloalkoxy, amino, alkylamino, dialkylamino or aninoalkyl group; and X₈is a bond, —(CH₂)_(n) where n is 1 to 3, —O—, —C(O)—, —S—, —S(O)—,—S(O)₂—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH—, or —NH—, wherein eachCH₂ in —(CH₂)_(n)—, —NHS(O)—, —S(O)—NH—, —NHSO₂—, —SO₂NH— or the —NH— isoptionally independently substituted with one or two substituentsselected from the group consisting of halogen, hydroxy, amino,alkylamino, dialkylamino, hydroxyalkyl, aminoalkyl, alkyl, haloalkyl,alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxyalkyl, carbocyclyl,halocarbocyclyl, carbocyclylalkyl and halocarbocyclylalkyl.
 2. Thecompound of claim 1, wherein at least one of Y and Z is optionallysubstituted naphthyl, indolyl, benzothiazolyl, benzoxazolyl,benzodioxolyl, benzothienyl, quinuclidinyl, quinolinyl,tetrahydroisoquinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl,indolizinyl, benzofuranyl, dihydrobenzofuranyl, chromonyl, coumarinyl,benzopyranyl, cinnolinyl, quinoxalinyl, indazolyl, pyrrolopyridyl,furopyridinyl, dihydroisoindolyl, dihydroquinazolinyl ortetrahydroquinolinyl.
 3. The compound of claim 1, wherein the compoundhas the structure of formula (IA):

wherein Ring A is an optionally substituted monocyclic 3 to 7-memberedcarbocyclylene, an optionally substituted monocyclic 3 to 7-memberedheterocyclylene ring, an optionally substituted bicyclic 7 to11-membered carbocyclylene or an optionally substituted bicyclic 7 to11-membered heterocyclylene ring; Ring B is an optionally substitutedmonocyclic 3 to 7-membered carbocyclylene, an optionally substitutedmonocyclic 3 to 7-membered heterocyclylene ring, an optionallysubstituted bicyclic 7 to 11-membered carbocyclylene or an optionallysubstituted bicyclic 7 to 11-membered heterocyclylene ring; and theLinker is the segment —X₃—X₄—X₅—X₆—.
 4. The compound of claim 3, whereinthe compound has the structure (IA-1) or (IA-2):

wherein variables Y, X₆, X₈ and Z are as defined for formula (I) inclaim 1; X₁ is a bond, —C(O)—, —C(S)—, —NH—, —S(O)—, —S(O)₂—, —NHS(O)—,—NHSO₂—, —(CH₂)_(n)— where n is 1 to 3, —O—CH₂—, —NHCH₂—, —S—CH₂—,—S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, and —CH₂—S(O)₂—, wherein each —NH—,—(CH₂)_(n)—, —O—CH₂—, —NHCH₂—, —S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—,—S(O)₂—CH₂—, and —CH₂—S(O)₂— are optionally substituted with oxo (═O) orone or more halogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups;Ring A is a 3- to 8-membered carbocyclic or heterocyclic ring where Q₅and Q₆ are independently N or CR₄ where R₄ is H, OH, halogen orC₁₋₃alkyl: W is O, S or an oxetane group; Q₁, Q₂, Q₃ and Q₄ are eachindependently C—H or a heteroatom selected from N, S or O; each R₁ isindependently halogen, cyano, hydroxyl, amino, alkylamino, dialkylamino,alkyl, haloalkyl, carbocyclyl, heterocyclyl, alkenyl, haloalkenyl,alkynyl or haloalkynyl; R₂ and R₃ are independently hydrogen, halogen,cyano, alkyl, haloalkyl or carbocyclyl; n is 0, 1, 2 or 3; m is 0, 1, 2,3 or 4; and r is 0 to
 5. 5. The compound of claim 1, wherein thecompound has the structure (IB):

wherein Ring B is an optionally substituted monocyclic 3- to 7-memberedcarbocyclylene, an optionally substituted monocyclic 3- to 7-memberedheterocyclylene ring, a bicyclic 7- to 11-membered carbocyclylene or a7- to 11-membered heterocyclylene ring; and the Linker is the segmentX₁—X₂—X₃—X₄—X₅—X₆—.
 6. The compound of claim 5, wherein the compound hasthe structure (IB-1), (IB-2), (IB-3) or (IB-4):

wherein Y, X₁, X₆, X₈ and Z are as defined above for formula (I) inclaim 1; W and W′ are each independently O or S; Q₁, Q₂, Q₃ and Q₄ areeach independently C—H or a heteroatom selected from N, S or O; Ring Ais a monocyclic 3- to 7-membered carbocyclic or heterocyclic ring or a7- to 11-membered carbocyclic or heterocyclic ring; R and R′ are eachindependently hydrogen, alkyl, haloalkyl or arylalkyl; each R₁ isindependently halogen, cyano, hydroxyl, amino, alkylamino, dialkylamino,alkyl, haloalkyl, carbocyclyl, heterocyclyl, alkenyl, haloalkenyl,alkynyl or haloalkynyl; R₂ and R₃ are independently hydrogen, halogen,cyano, alkyl, haloalkyl or carbocyclyl; n is 0, 1, 2 or 3; r is 0, 1, 2,3 or 4; and the dotted lines in the ring represent single or doublebonds.
 7. The compound of claim 1, wherein the compound has thestructure (IC):

wherein Ring A is an optionally substituted 5- to 7-memberedcarbocyclylene or an optionally substituted 5- to 7-memberedheterocyclylene ring; and the Linker is the segment —X₃—X₄—X₅—X₆—X₇—X₈—.8. The compound of claim 7, wherein the compound has the formula (IC-1):

wherein Y, X₈ and Z are as defined for formula (I) in claim 1; Ring A isa 3 to 8-membered monocyclic carbocyclic or heterocylic ring wherein Q₅and Q₆ are independently N or CR₄ where R₄ is H, halogen, OH orC₁₋₃alkyl; X₁ is a bond, —C(O)—, —C(S)—, —NH—, —S(O)—, —S(O)₂—,—(CH₂)_(n)— where n is 1 to 3, —O—CH₂—, —NHCH₂—, —S—CH₂—, —S(O)—CH₂—,—CH₂—S(O)—, —S(O)₂—CH₂—, or —CH₂—S(O)₂—, wherein each —NH—, —(CH₂)_(n)—,—O—CH₂—, —NHCH₂—, —S—CH₂—, —S(O)—CH₂—, —CH₂—S(O)—, —S(O)₂—CH₂—, and—CH₂—S(O)₂— are optionally substituted with oxo (═O) or one or morehalogen, cyano, alkyl, haloalkyl, cycloalkyl or aryl groups; W is O orS; R₂ and R₃ are independently hydrogen, halogen, cyano, alkyl,haloalkyl or carbocyclyl; and n is 1, 2 or
 3. 9. A composition for thetreatment and prevention of a parasitic infection or infestation in ananimal, comprising an effective amount of at least one anthelminticcompound of any one of claims 1 to 8 in combination with apharmaceutically acceptable carrier.
 10. The composition of claim 9,wherein the composition comprises an additional parasiticidal activeagent.
 11. A method for the treatment and prevention of a parasiticinfection or infestation in an animal, comprising administering aneffective amount of the compound of any one of claims 1 to 8 to theanimal.
 12. Use of a compound of any one of claims 1 to 8 in themanufacture of a medicament for the treatment of a parasitic infestationor infection in an animal.
 13. A compound of any one of claims 1 to 8for use in the treatment or prevention of a parasitic infestation orinfection in an animal.